Substituted quinoxalines as sodium channel modulators

ABSTRACT

The invention relates to compounds of formula I or pharmaceutically acceptable salts thereof, useful as inhibitors of sodium channels: 
                         
The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders, including pain.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 61/759,300, filed Jan. 31, 2013, the entire contents ofwhich are incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

The invention relates to compounds useful as inhibitors of sodiumchannels. The invention also provides pharmaceutically acceptablecompositions comprising the compounds of the invention and methods ofusing the compositions in the treatment of various disorders includingpain.

BACKGROUND OF THE INVENTION

Pain is a protective mechanism that allows healthy animals to avoidtissue damage and to prevent further damage to injured tissue.Nonetheless there are many conditions where pain persists beyond itsusefulness, or where patients would benefit from inhibition of pain.Neuropathic pain is a form of chronic pain caused by an injury to thesensory nerves (Dieleman, J. P., et al., Incidence rates and treatmentof neuropathic pain conditions in the general population. Pain, 2008.137(3): p. 681-8). Neuropathic pain can be divided into two categories,pain caused by generalized metabolic damage to the nerve and pain causedby a discrete nerve injury. The metabolic neuropathies include postherpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy.Discrete nerve injuries indications include post amputation pain,post-surgical nerve injury pain, and nerve entrapment injuries likeneuropathic back pain.

Voltage-gated sodium channels (Na_(V)'s) play a critical role in painsignaling. Na_(V)'s are key biological mediators of electrical signalingas they are the primary mediators of the rapid upstroke of the actionpotential of many excitable cell types (e.g. neurons, skeletal myocytes,cardiac myocytes). The evidence for the role of these channels in normalphysiology, the pathological states arising from mutations in sodiumchannel genes, preclinical work in animal models, and the clinicalpharmacology of known sodium channel modulating agents all point to thecentral role of Na_(V)'s in pain sensation (Rush, A. M. and T. R.Cummins, Painful Research: Identification of a Small-Molecule Inhibitorthat Selectively Targets Na _(V)1.8 Sodium Channels. Mol Interv, 2007.7(4): p. 192-5); England, S., Voltage-gated sodium channels: the searchfor subtype-selective analgesics. Expert Opin Investig Drugs 17 (12), p.1849-64 (2008); Krafte, D. S. and Bannon, A. W., Sodium channels andnociception: recent concepts and therapeutic opportunities. Curr OpinPharmacol 8 (1), p. 50-56 (2008)). Na_(V)'s are the primary mediators ofthe rapid upstroke of the action potential of many excitable cell types(e.g. neurons, skeletal myocytes, cardiac myocytes), and thus arecritical for the initiation of signaling in those cells (Hille, Bertil,Ion Channels of Excitable Membranes, Third ed. (Sinauer Associates,Inc., Sunderland, Mass., 2001)). Because of the role Na_(V)'s play inthe initiation and propagation of neuronal signals, antagonists thatreduce Na_(V) currents can prevent or reduce neural signaling and Na_(V)channels have long been considered likely targets to reduce pain inconditions where hyper-excitability is observed (Chahine, M., Chatelier,A., Babich, 0., and Krupp, J. J., Voltage-gated sodium channels inneurological disorders. CNS Neurol Disord Drug Targets 7 (2), p. 144-58(2008)). Several clinically useful analgesics have been identified asinhibitors of Na_(V) channels. The local anesthetic drugs such aslidocaine block pain by inhibiting Na_(V) channels, and other compounds,such as carbamazepine, lamotrigine, and tricyclic antidepressants thathave proven effective at reducing pain have also been suggested to actby sodium channel inhibition (Soderpalm, B., Anticonvulsants: aspects oftheir mechanisms of action. Eur J Pain 6 Suppl A, p. 3-9 (2002); Wang,G. K., Mitchell, J., and Wang, S. Y., Block of persistent late Na⁺currents by antidepressant sertraline and paroxetine. J Membr Biol 222(2), p. 79-90 (2008)).

The Na_(V)'s form a subfamily of the voltage-gated ion channelsuper-family and comprises 9 isoforms, designated Nav1.1-Nav1.9. Thetissue localizations of the nine isoforms vary greatly. Nav1.4 is theprimary sodium channel of skeletal muscle, and Nav1.5 is primary sodiumchannel of cardiac myocytes. Na_(V)'s 1.7, 1.8 and 1.9 are primarilylocalized to the peripheral nervous system, while Na_(V)'s 1.1, 1.2,1.3, and 1.6 are neuronal channels found in both the central andperipheral nervous systems. The functional behaviors of the nineisoforms are similar but distinct in the specifics of theirvoltage-dependent and kinetic behavior (Catterall, W. A., Goldin, A. L.,and Waxman, S. G., International Union of Pharmacology. XLVII.Nomenclature and structure-function relationships of voltage-gatedsodium channels. Pharmacol Rev 57 (4), p. 397 (2005)).

Immediately upon their discovery, Na_(V)1.8 channels were identified aslikely targets for analgesia (Akopian, A. N., L. Sivilotti, and J. N.Wood, A tetrodotoxin-resistant voltage-gated sodium channel expressed bysensory neurons. Nature, 1996. 379(6562): p. 257-62). Since then,Na_(V)1.8 has been shown to be the most significant carrier of thesodium current that maintains action potential firing in small DRGneurons (Blair, N. T. and B. P. Bean, Roles of tetrodotoxin(TTX)-sensitive Na+ current, TTX-resistant Na⁺ current, and Ca²⁺ currentin the action potentials of nociceptive sensory neurons. J Neurosci.,2002. 22(23): p. 10277-90). Na_(V)1.8 is essential for spontaneousfiring in damaged neurons, like those that drive neuropathic pain (Roza,C., et al., The tetrodotoxin-resistant Na⁺ channel Na_(V)1.8 isessential for the expression of spontaneous activity in damaged sensoryaxons of mice. J. Physiol., 2003. 550(Pt 3): p. 921-6; Jarvis, M. F., etal., A-803467, a potent and selective Na_(V)1.8 sodium channel blocker,attenuates neuropathic and inflammatory pain in the rat. Proc Natl AcadSci. USA, 2007. 104(20): p. 8520-5; Joshi, S. K., et al., Involvement ofthe TTX-resistant sodium channel Nav1.8 in inflammatory and neuropathic,but not post-operative, pain states. Pain, 2006. 123(1-2): pp. 75-82;Lai, J., et al., Inhibition of neuropathic pain by decreased expressionof the tetrodotoxin-resistant sodium channel, Na_(V)1.8. Pain, 2002.95(1-2): p. 143-52; Dong, X. W., et al., Small interfering RNA-mediatedselective knockdown of Na(_(V))1.8 tetrodotoxin-resistant sodium channelreverses mechanical allodynia in neuropathic rats. Neuroscience, 2007.146(2): p. 812-21; Huang, H. L., et al., Proteomic profiling of neuromasreveals alterations in protein composition and local protein synthesisin hyper-excitable nerves. Mol Pain, 2008. 4: p. 33; Black, J. A., etal., Multiple sodium channel isoforms and mitogen-activated proteinkinases are present in painful human neuromas. Ann Neurol, 2008. 64(6):p. 644-53; Coward, K., et al, Immunolocalization of SNS/PN3 and NaN/SNS2sodium channels in human pain states. Pain, 2000. 85(1-2): p. 41-50;Yiangou, Y., et al., SNS/PN3 and SNS2/NaN sodium channel-likeimmunoreactivity in human adult and neonate injured sensory nerves. FEBSLett, 2000. 467(2-3): p. 249-52; Ruangsri, S., et al., Relationship ofaxonal voltage-gated sodium channel 1.8 (Na_(V)1.8) mRNA accumulation tosciatic nerve injury-induced painful neuropathy in rats. J Biol Chem.286(46): p. 39836-47). The small DRG neurons where Na_(V)1.8 isexpressed include the nociceptors critical for pain signaling. Na_(V)1.8is the primary channel that mediates large amplitude action potentialsin small neurons of the dorsal root ganglia (Blair, N. T. and B. P.Bean, Roles of tetrodotoxin (TTX)-sensitive Na⁺ current, TTX-resistantNa⁺ current, and Ca²⁺ current in the action potentials of nociceptivesensory neurons. J Neurosci., 2002. 22(23): p. 10277-90). Na_(V)1.8 isnecessary for rapid repetitive action potentials in nociceptors, and forspontaneous activity of damaged neurons. (Choi, J. S. and S. G. Waxman,Physiological interactions between Na_(V)1.7 and Na_(V)1.8 sodiumchannels: a computer simulation study. J Neurophysiol. 106(6): p.3173-84; Renganathan, M., T. R. Cummins, and S. G. Waxman, Contributionof Na_((v))1.8 sodium channels to action potential electrogenesis in DRGneurons. J Neurophysiol., 2001. 86(2): p. 629-40; Roza, C., et al., Thetetrodotoxin-resistant Na⁺ channel Na_(V)1.8 is essential for theexpression of spontaneous activity in damaged sensory axons of mice. JPhysiol., 2003. 550(Pt 3): p. 921-6). In depolarized or damaged DRGneurons, Na_(V)1.8 appears to be the primary driver ofhyper-excitability (Rush, A. M., et al., A single sodium channelmutation produces hyper- or hypoexcitability in different types ofneurons. Proc Nati Acad Sci USA, 2006. 103(21): p. 8245-50). In someanimal pain models, Na_(V)1.8 mRNA expression levels have been shown toincrease in the DRG (Sun, W., et al., Reduced conduction failure of themain axon of polymodal nociceptive C-fibres contributes to painfuldiabetic neuropathy in rats. Brain. 135(Pt 2): p. 359-75; Strickland, I.T., et al., Changes in the expression of Na_(V)1.7, Na_(V)1.8 andNa_(V)1.9 in a distinct population of dorsal root ganglia innervatingthe rat knee joint in a model of chronic inflammatory joint pain. Eur JPain, 2008. 12(5): p. 564-72; Qiu, F., et al., Increased expression oftetrodotoxin-resistant sodium channels Na_(V)1.8 and Na_(V)1.9 withindorsal root ganglia in a rat model of bone cancer pain. Neurosci. Lett.512(2): p. 61-6).

The primary drawback to the known Na_(V) inhibitors is their poortherapeutic window, and this is likely a consequence of their lack ofisoform selectivity. Since Na_(V)1.8 is primarily restricted to theneurons that sense pain, selective Na_(V)1.8 blockers are unlikely toinduce the adverse events common to non-selective Na_(V) blockers.Accordingly, there remains a need to develop additional Na_(V) channelantagonists preferably those that are more Nav1.8 selective and morepotent with increased metabolic stability and with fewer side effects.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable salts and compositions thereof, are usefulas inhibitors of voltage-gated sodium channels.

These compounds have the general formula I:

or a pharmaceutically acceptable salt thereof.

These compounds and pharmaceutically acceptable salts and compositionsare useful for treating or lessening the severity of a variety ofdiseases, disorders, or conditions, including, but not limited to,chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acutepain, inflammatory pain, cancer pain, idiopathic pain, multiplesclerosis, Charcot-Marie-Tooth syndrome, incontinence or cardiacarrhythmia.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the invention provides compounds of formula I:

-   or a pharmaceutically acceptable salt thereof,-   wherein, independently for each occurrence:-   Y is C or N;-   Ar¹ is a 5-6 membered aromatic monocyclic ring having 0-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur,    wherein said ring is optionally fused to a 5-membered monocyclic    aromatic ring having 0-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, wherein Ar¹ has m substituents, each    independently selected from —WR^(W);-   m is an integer from 0 to 5 inclusive;-   W is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—, —CO—, —S—, —SO—, —SO₂—;-   R^(W) is absent, H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, OCF₃, or a    3-6 membered saturated, partially unsaturated, or fully unsaturated    monocyclic ring having 0-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, R′ is C₁-C₆ alkyl;-   R¹ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen and wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R² is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R³ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁴ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁵ is H, halogen, CN, or —X—R^(X);-   R^(5′) is H, halogen, CN, or —X—R^(X);-   R⁶ is H, halogen, CN, or —X—R^(X);-   R^(6′) is H, halogen, CN, or —X—R^(X);-   R⁷ is H, halogen, CN, or —X—R^(X);-   X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—; and-   R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to two    non-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced    with —O— and said C₃-C₈ cycloaliphatic is substituted with 0-3    substituents selected from halogen and C₁-C₄ alkyl.

For purposes of this invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75th Ed. Additionally, generalprinciples of organic chemistry are described in “Organic Chemistry,”Thomas Sorrell, University Science Books, Sausalito: 1999, and “March'sAdvanced Organic Chemistry,” 5^(th) Ed., Ed.: Smith, M. B. and March,J., John Wiley & Sons, New York: 2001, the entire contents of which arehereby incorporated by reference.

As described herein, compounds of the invention can optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. As described herein, the variables informula I encompass specific groups, such as, for example, alkyl andcycloalkyl. As one of ordinary skill in the art will recognize,combinations of substituents envisioned by this invention are thosecombinations that result in the formation of stable or chemicallyfeasible compounds. The term “stable,” as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and preferablytheir recovery, purification, and use for one or more of the purposesdisclosed herein. In some embodiments, a stable compound or chemicallyfeasible compound is one that is not substantially altered when kept ata temperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

The phrase “optionally substituted” may be used interchangeably with thephrase “substituted or unsubstituted.” In general, the term“substituted,” whether preceded by the term “optionally” or not, refersto the replacement of hydrogen radicals in a given structure with theradical of a specified substituent. Specific substituents are describedabove in the definitions and below in the description of compounds andexamples thereof. Unless otherwise indicated, an optionally substitutedgroup can have a substituent at each substitutable position of thegroup, and when more than one position in any given structure can besubstituted with more than one substituent selected from a specifiedgroup, the substituent can be either the same or different at everyposition. A ring substituent, such as a heterocycloalkyl, can be boundto another ring, such as a cycloalkyl, to form a spiro-bicyclic ringsystem, e.g., both rings share one common atom. As one of ordinary skillin the art will recognize, combinations of substituents envisioned bythis invention are those combinations that result in the formation ofstable or chemically feasible compounds.

The phrase “up to,” as used herein, refers to zero or any integer numberthat is equal or less than the number following the phrase. For example,“up to 4” means any one of 0, 1, 2, 3, and 4.

The term “aliphatic,” “aliphatic group” or “alkyl” as used herein, meansa straight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation. Unless otherwise specified,aliphatic groups contain 1-20 aliphatic carbon atoms. In someembodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. Inother embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms.In still other embodiments, aliphatic groups contain 1-6 aliphaticcarbon atoms, and in yet other embodiments aliphatic groups contain 1-4aliphatic carbon atoms. Suitable aliphatic groups include, but are notlimited to, linear or branched, substituted or unsubstituted alkyl,alkenyl, alkynyl groups.

The terms “cycloaliphatic” or “cycloalkyl” mean a monocyclic hydrocarbonring, or a polycyclic hydrocarbon ring system that is completelysaturated or that contains one or more units of unsaturation, but whichis not aromatic and has a single point of attachment to the rest of themolecule. The term “polycyclic ring system,” as used herein, includesbicyclic and tricyclic 4- to 12-membered structures that form at leasttwo rings, wherein the two rings have at least one atom in common (e.g.,2 atoms in common) including fused, bridged, or spirocyclic ringsystems.

The term “halogen” or “halo” as used herein, means F, Cl, Br or I.Unless otherwise specified, the term “heterocycle,” “heterocyclyl,”“heterocycloaliphatic,” “heterocycloalkyl,” or “heterocyclic” as usedherein means non-aromatic, monocyclic, bicyclic, or tricyclic ringsystems in which one or more ring atoms in one or more ring members isan independently selected heteroatom. Heterocyclic ring can be saturatedor can contain one or more unsaturated bonds. In some embodiments, the“heterocycle,” “heterocyclyl,” “heterocycloaliphatic,”“heterocycloalkyl,” or “heterocyclic” group has three to fourteen ringmembers in which one or more ring members is a heteroatom independentlyselected from oxygen, sulfur, nitrogen, or phosphorus, and each ring inthe ring system contains 3 to 7 ring members.

The term “heteroatom” means oxygen, sulfur, nitrogen, phosphorus, orsilicon (including, any oxidized form of nitrogen, sulfur, phosphorus,or silicon; the quaternized form of any basic nitrogen or; asubstitutable nitrogen of a heterocyclic ring, for example N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as inN-substituted pyrrolidinyl)).

The term “unsaturated,” as used herein, means that a moiety has one ormore units of unsaturation but is not aromatic.

The term “alkoxy,” or “thioalkyl,” as used herein, refers to an alkylgroup, as previously defined, attached to the principal carbon chainthrough an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic,bicyclic, and tricyclic ring systems having a total of five to fourteenring carbon atoms, wherein at least one ring in the system is aromaticand wherein each ring in the system contains 3 to 7 ring carbon atoms.The term “aryl” may be used interchangeably with the term “aryl ring.”

The term “heteroaryl,” used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy,” refers to monocyclic, bicyclic,and tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic, at leastone ring in the system contains one or more heteroatoms, and whereineach ring in the system contains 3 to 7 ring members. The term“heteroaryl” may be used interchangeably with the term “heteroaryl ring”or the term “heteroaromatic.”

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention. Unless otherwise stated, alltautomeric forms of the compounds of the invention are within the scopeof the invention. Thus, included within the scope of the invention aretautomers of compounds of formula I. The structures also includezwitterionic forms of the compounds or salts of formula I whereappropriate. Examples of tautomeric forms include those depicted below:

Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched or isotopically-labeled atoms. Theisotopically-labeled compounds may have one or more atoms replaced by anatom having an atomic mass or mass number usually found in nature.Examples of isotopes present in compounds of formula I include isotopesof hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine andchlorine, such as, but not limited to, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O,³⁵S and ¹⁸F. Certain isotopically-labeled compounds of formula I, inaddition to being useful as therapeutic agents, are also useful in drugand/or substrate tissue distribution assays, as analytical tools or asprobes in other biological assays. In one aspect of the presentinvention, tritiated (e.g., ³H) and carbon-14 (e.g., ¹⁴C) isotopes areuseful given their ease of detectability. In another aspect of thepresent invention, replacement of one or more hydrogen atoms withheavier isotopes such as deuterium, (e.g., ²H) can afford certaintherapeutic advantages.

In the formulas and drawings, a line transversing a ring and bonded toan R group such as in

means that the R group, i.e. the WR^(W) can be attached to anysubstitutable ring atom on either ring of the bicyclic ring system.

Within a definition of a term as, for example, X, R^(X), R¹, R², R³, R⁴,or W when a CH₂ unit or, interchangeably, methylene unit may bereplaced, for example, by —O—, it is meant to include any CH₂ unit,including a CH₂ within a terminal methyl group. For example, CH₂CH₂CH₂OHis within the definition of C₁-C₆ alkyl wherein up to two non-adjacentCH₂ units may be replaced by —O— because the CH₂ unit of the terminalmethyl group has been replaced by —O—.

In one embodiment, the invention features a compound of formula I andthe attendant definitions, wherein Y is C. In another embodiment, Y isN.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein Ar¹ is selected from:

-   wherein ring A₁ is a 5-6 membered aromatic monocyclic ring having    0-4 heteroatoms independently selected from nitrogen, oxygen, or    sulfur; or-   A₁ and A₂, together, form an 8-9 membered aromatic, bicyclic ring,    wherein each ring contains 0-4 heteroatoms independently selected    from nitrogen, oxygen, or sulfur.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein Ar¹ is

and A₁ is a 6 membered aromatic ring having 0-4 heteroatoms,independently selected from nitrogen, oxygen, or sulfur. In anotherembodiment, A₁ is phenyl. In another embodiment, A₁ is a 6 memberedaromatic ring having 1 or 2 heteroatoms, independently selected fromnitrogen. In another embodiment, A₁ is pyridyl, pyrimidinyl, pyrazinylor triazinyl.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein Ar¹ is

and A₁ is a 5-membered aromatic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In anotherembodiment, A₁ is a 5-membered aromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In anotherembodiment, A₁ is pyrrolyl, pyrazolyl, thiazolyl, thiadiazolyl,imidazolyl, oxazolyl, triazolyl, or tetrazolyl.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein Ar¹ is

A₁ is phenyl, and A₂ is a 5-membered aromatic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Inanother embodiment, A₂ is a 5-membered aromatic ring having 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur. Inanother embodiment, A₂ is pyrrolyl, pyrazolyl, thiazolyl, thiadiazolyl,imidazolyl, oxazolyl, or triazolyl.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein m is zero. In another embodiment,m is an integer from 1 to 5. In another embodiment, m is 1. In anotherembodiment, m is 2. In another embodiment, m is 3. In anotherembodiment, m is 4. In another embodiment, m is 5.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein W is a bond and R^(W) is halogen,OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃, In another embodiment, W is a bondand R^(W) is halogen. In another embodiment, W is a bond and R^(W) isOH. In another embodiment, W is a bond and R^(W) is NH₂, In anotherembodiment, W is a bond and R^(W) is NHR′. In another embodiment, W is abond and R^(W) is CN. In another embodiment, W is a bond and R^(W) isCF₃, In another embodiment, W is a bond and R^(W) is OCF₃.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein W is C₁-C₆ alkyl wherein saidC₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. In another embodiment, Wis CH₃, CH₂CH₃, CH₂CH₂CH₃, or isopropyl. In another embodiment, W isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen,wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O—, —CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. Inanother embodiment, W is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, or O-isopropyl. Inanother embodiment, W is OCH₂CF₃, OCH₂CH₂CH₂CF₃, or OCHF₂. In anotherembodiment, W is OCH₂CH₂OCH₃, CH₂OH, OC(CH₃)₃, or CH₂CH₂OCH₃.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein W is C₁-C₆ alkyl wherein saidC₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂,CN, CF₃, or OCF₃. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or—SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO—, or —SO₂—, and R^(W) is H, OH, NH₂, or NHR′. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H. In another embodiment, W is C₁ alkylwherein one CH₂ unit of said C₁ alkyl is replaced with —CO— and R^(W) isOH. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁alkyl is replaced with —CO— and R^(W) is NH₂. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—and R^(W) is NHR′. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is H, OH, NH₂, orNHR′. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of saidC₁ alkyl is replaced with —SO₂— and R^(W) is H. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —SO₂—and R^(W) is OH. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is NH₂. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —SO₂— and R^(W) is NHR′.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein W is C₁-C₆ alkyl wherein saidC₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) absent. In another embodiment, W isC₂ alkyl wherein one CH₂ unit of said C₂ alkyl may be replaced with —O—,—CO—, —S—, —SO—, —SO₂—, and R^(W) is absent. In another embodiment, W isC₂ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—, or—SO₂—, and R^(W) is absent.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein W is a bond and R^(W) is a 3-6membered saturated, partially unsaturated, or fully unsaturatedmonocyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In another embodiment, W is a bond andR^(W) is a 5-membered aromatic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In another embodiment, W is abond and R^(W) is a 5-membered aromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In anotherembodiment, W is a bond and R^(W) is pyrrolyl, pyrazolyl, thiazolyl,thiadiazolyl, imidazolyl, oxazolyl, triazolyl, or tetrazolyl.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R¹ is H. In another embodiment,R¹ is halogen. In another embodiment, R¹ is CN. In another embodiment,R¹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen. In another embodiment, R¹ is CF₃.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R² is H. In another embodiment,R² is halogen. In another embodiment, R² is Cl. In another embodiment,R² is F. In another embodiment, R² is CN. In another embodiment, R² isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R² is CF₃. In another embodiment, R² is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen wherein one CH₂unit of said C₁-C₆ alkyl is replaced with —O—. In another embodiment, R²is OCF₃. In another embodiment, R² is F, Cl, CN, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R³ is H. In another embodiment,R³ is halogen. In another embodiment, R³ is Cl. In another embodiment,R³ is F. In another embodiment, R³ is CN. In another embodiment, R³ isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R³ is t-butyl. In another embodiment, R³ is CF₃. Inanother embodiment, R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R⁴ is H. In another embodiment,R⁴ is halogen. In another embodiment, R⁴ is CN. In another embodiment,R⁴ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen. In another embodiment, R⁴ is CF₃.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R¹, R², R³, and R⁴ is H.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R⁵ is H. In another embodiment,R⁵ is halogen. In another embodiment, R⁵ is Cl. In another embodiment,R⁵ is F. In another embodiment, R⁵ is CN. In another embodiment, R⁵ is—X—R^(X). In another embodiment, R⁵ is —X—R^(X) wherein R^(X) is absent.In another embodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R⁵ is CH₃. In another embodiment, R⁵ is —X—R^(X)wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁵ is OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, or OCH(CH₃)₂. In another embodiment, R⁵ is OCH₃. In anotherembodiment, R⁵ is CH₂OH. In another embodiment, R⁵ is OCF₃. In anotherembodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R^(5′) is H. In anotherembodiment, R^(5′) is halogen. In another embodiment, R^(5′) is Cl. Inanother embodiment, R^(5′) is F. In another embodiment, R^(5′) is CN. Inanother embodiment, R^(5′) is —X—R^(X). In another embodiment, R^(5′) is—X—R^(X) wherein R^(X) is absent. In another embodiment, R^(5′) is—X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆alkyl is substituted with 0-6 halogen. In another embodiment, R^(5′) isCH₃. In another embodiment, R^(5′) is —X—R^(X) wherein R^(X) is absentand X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O—.In another embodiment, R^(5′) is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, orOCH(CH₃)₂. In another embodiment, R^(5′) is OCH₃. In another embodiment,R^(5′) is CH₂OH. In another embodiment, R^(5′) is OCF₃. In anotherembodiment, R^(5′) is OCHF₂.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, R⁶ is H. In another embodiment, R⁶ ishalogen. In another embodiment, R⁶ is Cl. In another embodiment, R⁶ isF. In another embodiment, R⁶ is CN. In another embodiment, R⁶ is—X—R^(X). In another embodiment, R⁶ is —X—R^(X) wherein R^(X) is absent.In another embodiment, R⁶ is —X—R^(X) wherein R^(X) is absent and X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R⁶ is CH₃. In another embodiment, R⁶ is —X—R^(X)wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁶ is OCH₃.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R^(6′) is H. In anotherembodiment, R^(6′) is halogen. In another embodiment, R^(6′) is Cl. Inanother embodiment, R^(6′) is F. In another embodiment, R^(6′) is CN. Inanother embodiment, R^(6′) is —X—R^(X). In another embodiment, R^(6′) is—X—R^(X) wherein R^(X) is absent. In another embodiment, R^(6′) is—X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆alkyl is substituted with 0-6 halogen. In another embodiment, R^(6′) isCH₃. In another embodiment, R^(6′) is —X—R^(X) wherein R^(X) is absentand X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O—.In another embodiment, R^(6′) is OCH₃.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R⁷ is H. In another embodiment,R⁷ is halogen. In another embodiment, R⁷ is Cl. In another embodiment,R⁷ is F. In another embodiment, R⁷ is CN. In another embodiment, R⁷ is—X—R^(X). In another embodiment, R⁷ is —X—R^(X) wherein R^(X) is absent.In another embodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. Inanother embodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X)wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formula Iwherein R⁷ is —X—R^(X) wherein X is a bond and R^(X) is C₃-C₈cycloaliphatic and said C₃-C₈ cycloaliphatic is substituted with 0-3substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is a bond and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R⁷ is —X—R^(X) wherein X is C₁-C₆alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen whereinone CH₂ unit of said C₁-C₆ alkyl is replaced with —O— and R^(X) is C₃-C₈cycloaliphatic and said C₃-C₈ cycloaliphatic is substituted with up 0-3substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is OCH₂ and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein ring A is selected from:

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R¹ is H or C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen. In another embodiment,R¹ is CF₃.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R² is H, halogen, or C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen and wherein oneCH₂ unit of said C₁-C₆ alkyl is replaced with —O—. In anotherembodiment, R² is F, Cl, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R³ is H, halogen or C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R³ is t-butyl, Cl, CF₃ or CF₂CF₃.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R⁴ is H, halogen or C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁴ is CF₃.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R¹, R², R³ and R⁴ are H.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R⁵ and R⁷ are each independentlyhalogen, or —X—R^(X) and R^(5′), R⁶, and R^(6′) are each hydrogen. Inanother embodiment, R⁵ and R⁷ are each independently F, Cl, CH₃, OCF₃,or OCH₃.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein ring A is selected from:

In another embodiment, ring A is selected from:

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein Ar¹ is

A₁ is a 6 membered aromatic ring having 0-4 heteroatoms, independentlyselected from nitrogen, oxygen, or sulfur, m is 1, W is a bond or C₁-C₆alkyl wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl maybe replaced with —CO—, or —SO₂—, and R^(W) is selected from H, OH, NH₂,or CN.

In another embodiment, A₁ is phenyl or pyridyl, m is 1 and WR^(W) isselected from H, SO₂NH₂, CO₂H, SO₂CH₃, CONH₂ or CN.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein Ar¹ is

A₁ is phenyl, A₂ is a 5-membered aromatic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, m is 1, W is abond or C₁-C₆ alkyl wherein up to two non-adjacent CH₂ units of saidC₁-C₆ alkyl may be replaced with —CO—, or —SO₂—, and R^(W) is selectedfrom H, OH, NH₂, or CN.

In another embodiment, A₁ is phenyl, A₂ is pyrrolyl, pyrazolyl,thiazolyl, thiadiazolyl, imidazolyl, oxazolyl, or triazolyl, m is 1 andWR^(W) is selected from H or CO₂H.

In another aspect, the invention provides a compound of formula I-A:

-   or a pharmaceutically acceptable salt thereof,-   wherein, independently for each occurrence:-   Y is C or N;-   A₁ is a 5-6 membered aromatic ring having 0-4 heteroatoms,    independently selected from nitrogen, oxygen, or sulfur;-   m is an integer from 0 to 5 inclusive;-   W is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or —SO₂—;-   R^(W) is absent, H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, OCF₃, or a    3-6 membered saturated, partially unsaturated, or fully unsaturated    monocyclic ring having 0-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   R′ is C₁-C₆ alkyl;-   R¹ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen and wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R² is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R³ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁴ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁵ is H, halogen, CN, or —X—R^(X);-   R^(5′) is H, halogen, CN, or —X—R^(X);-   R⁶ is H, halogen, CN, or —X—R^(X);-   R^(6′) is H, halogen, CN, or —X—R^(X);-   R⁷ is H, halogen, CN, or —X—R^(X);-   X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—; and-   R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to two    non-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced    with —O— and said C₃-C₈ cycloaliphatic is substituted with 0-3    substituents selected from halogen and C₁-C₄ alkyl.

In one embodiment, the invention features a compound of formula I-A andthe attendant definitions, wherein Y is C. In another embodiment, Y isN.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein A₁ is a 6 membered aromatic ringhaving 0-4 heteroatoms, independently selected from nitrogen, oxygen, orsulfur. In another embodiment, A₁ is phenyl. In another embodiment, A₁is a 6 membered aromatic ring having 1 or 2 heteroatoms, independentlyselected from nitrogen. In another embodiment, A₁ is pyridyl,pyrimidinyl, pyrazinyl or triazinyl.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein A₁ is a 5-membered aromatic ringhaving 0-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur. In another embodiment, A₁ is a 5-membered aromatic ring having1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.In another embodiment, A₁ is pyrrolyl, pyrazolyl, thiazolyl,thiadiazolyl, imidazolyl, oxazolyl, triazolyl, or tetrazolyl.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein ring A₁ is selected from:

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein m is zero. In another embodiment,m is an integer from 1 to 5. In another embodiment, m is 1. In anotherembodiment, m is 2. In another embodiment, m is 3. In anotherembodiment, m is 4. In another embodiment, m is 5.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein W is a bond and R^(W) is halogen,OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. In another embodiment, W is a bondand R^(W) is halogen. In another embodiment, W is a bond and R^(W) isOH. In another embodiment, W is a bond and R^(W) is NH₂. In anotherembodiment, W is a bond and R^(W) is NHR′. In another embodiment, W is abond and R^(W) is CN. In another embodiment, W is a bond and R^(W) isCF₃. In another embodiment, W is a bond and R^(W) is OCF₃.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein W is C₁-C₆ alkyl wherein saidC₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. In another embodiment, Wis CH₃, CH₂CH₃, CH₂CH₂CH₃, or isopropyl. In another embodiment, W isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen,wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O—, —CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. Inanother embodiment, W is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, or O-isopropyl. Inanother embodiment, W is OCH₂CF₃, OCH₂CH₂CH₂CF₃, or OCHF₂. In anotherembodiment, W is OCH₂CH₂OCH₃, CH₂OH, OC(CH₃)₃, or CH₂CH₂OCH₃.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein W is C₁-C₆ alkyl wherein saidC₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂,CN, CF₃, or OCF₃. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl may be replaced with —O—, —CO—, —S—, —SO—, —SO₂—,and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO—, or —SO₂—, and R^(W) is H, OH, NH₂, or NHR′. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H. In another embodiment, W is C₁ alkylwherein one CH₂ unit of said C₁ alkyl is replaced with —CO— and R^(W) isOH. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁alkyl is replaced with —CO— and R^(W) is NH₂. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—and R^(W) is NHR′. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is H, OH, NH₂, orNHR′. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of saidC₁ alkyl is replaced with —SO₂— and R^(W) is H. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —SO₂—and R^(W) is OH. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is NH₂. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —SO₂— and R^(W) is NHR′.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein W is C₁-C₆ alkyl wherein saidC₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) absent. In another embodiment, W isC₂ alkyl wherein one CH₂ unit of said C₂ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is absent. In another embodiment, Wis C₂ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—,or —SO₂—, and R^(W) is absent.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein W is a bond and R^(W) is a 3-6membered saturated, partially unsaturated, or fully unsaturatedmonocyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In another embodiment, W is a bond andR^(W) is a 5-membered aromatic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In another embodiment, W is abond and R^(W) is a 5-membered aromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In anotherembodiment, W is a bond and R^(W) is pyrrolyl, pyrazolyl, thiazolyl,thiadiazolyl, imidazolyl, oxazolyl, triazolyl, or tetrazolyl.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein ring A₁ is selected from:

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein R¹ is H. In another embodiment,R¹ is halogen. In another embodiment, R¹ is CN. In another embodiment,R¹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen. In another embodiment, R¹ is CF₃.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein R² is H. In another embodiment,R² is halogen. In another embodiment, R² is Cl. In another embodiment,R² is F. In another embodiment, R² is CN. In another embodiment, R² isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R² is CF₃. In another embodiment, R² is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen wherein one CH₂unit of said C₁-C₆ alkyl is replaced with —O—. In another embodiment, R²is OCF₃. In another embodiment, R² is F, Cl, CN, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein R³ is H. In another embodiment,R³ is halogen. In another embodiment, R³ is Cl. In another embodiment,R³ is F. In another embodiment, R³ is CN. In another embodiment, R³ isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R³ is t-butyl. In another embodiment, R³ is CF₃. Inanother embodiment, R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein R⁴ is H. In another embodiment,R⁴ is halogen. In another embodiment, R⁴ is CN. In another embodiment,R⁴ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen. In another embodiment, R⁴ is CF₃.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein R¹, R², R³, and R⁴ is H.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein R⁵ is H. In another embodiment,R⁵ is halogen. In another embodiment, R⁵ is Cl. In another embodiment,R⁵ is F. In another embodiment, R⁵ is CN. In another embodiment, R⁵ is—X—R^(X). In another embodiment, R⁵ is —X—R^(X) wherein R^(X) is absent.In another embodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R⁵ is CH₃. In another embodiment, R⁵ is —X—R^(X)wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁵ is OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, or OCH(CH₃)₂. In another embodiment, R⁵ is OCH₃. In anotherembodiment, R⁵ is CH₂OH. In another embodiment, R⁵ is OCF₃. In anotherembodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein R^(5′) is H. In anotherembodiment, R^(5′) is halogen. In another embodiment, R^(5′) is Cl. Inanother embodiment, R^(5′) is F. In another embodiment, R^(5′) is CN. Inanother embodiment, R^(5′) is —X—R^(X). In another embodiment, R^(5′) is—X—R^(X) wherein R^(X) is absent. In another embodiment, R^(5′) is—X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆alkyl is substituted with 0-6 halogen. In another embodiment, R^(5′) isCH₃. In another embodiment, R^(5′) is —X—R^(X) wherein R^(X) is absentand X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O—.In another embodiment, R^(5′) is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, orOCH(CH₃)₂. In another embodiment, R^(5′) is OCH₃. In another embodiment,R^(5′) is CH₂OH. In another embodiment, R^(5′) is OCF₃. In anotherembodiment, R^(5′) is OCHF₂.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, R⁶ is H. In another embodiment, R⁶ ishalogen. In another embodiment, R⁶ is Cl. In another embodiment, R⁶ isF. In another embodiment, R⁶ is CN. In another embodiment, R⁶ is—X—R^(X). In another embodiment, R⁶ is —X—R^(X) wherein R^(X) is absent.In another embodiment, R⁶ is —X—R^(X) wherein R^(X) is absent and X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R⁶ is CH₃. In another embodiment, R⁶ is —X—R^(X)wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁶ is OCH₃.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein R^(6′) is H. In anotherembodiment, R^(6′) is halogen. In another embodiment, R^(6′) is Cl. Inanother embodiment, R^(6′) is F. In another embodiment, R^(6′) is CN. Inanother embodiment, R^(6′) is —X—R^(X). In another embodiment, R^(6′) is—X—R^(X) wherein R^(X) is absent. In another embodiment, R^(6′) is—X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆alkyl is substituted with 0-6 halogen. In another embodiment, R^(6′) isCH₃. In another embodiment, R^(6′) is —X—R^(X) wherein R^(X) is absentand X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O—.In another embodiment, R^(6′) is OCH₃.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein R⁷ is H. In another embodiment,R⁷ is halogen. In another embodiment, R⁷ is Cl. In another embodiment,R⁷ is F. In another embodiment, R⁷ is CN. In another embodiment, R⁷ is—X—R^(X). In another embodiment, R⁷ is —X—R^(X) wherein R^(X) is absent.In another embodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. Inanother embodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X)wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formula I-Awherein R⁷ is —X—R^(X) wherein X is a bond and R^(X) is C₃-C₈cycloaliphatic and said C₃-C₈ cycloaliphatic is substituted with 0-3substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is a bond and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein R⁷ is —X—R^(X) wherein X is C₁-C₆alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen whereinone CH₂ unit of said C₁-C₆ alkyl is replaced with —O— and R^(X) is C₃-C₈cycloaliphatic and said C₃-C₈ cycloaliphatic is substituted with up 0-3substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is OCH₂ and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein ring A is selected from:

In another embodiment ring A is selected from:

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein R¹, R², R³ and R⁴ are H.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein R⁵ and R⁷ are each independentlyhalogen, or —X—R^(X) and R^(5′), R⁶, and R^(6′) are each hydrogen. Inanother embodiment, R⁵ and R⁷ are each independently F, Cl, CH₃, OCF₃,or OCH₃.

In another aspect, the invention provides a compound of formula I-B:

-   or a pharmaceutically acceptable salt thereof,-   wherein, independently for each occurrence:-   Y is C or N;-   m is an integer from 0 to 5 inclusive;-   W is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or —SO₂—;-   R^(W) is absent, H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, OCF₃, or a    3-6 membered saturated, partially unsaturated, or fully unsaturated    monocyclic ring having 0-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   R′ is C₁-C₆ alkyl;-   R¹ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen and wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R² is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R³ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁴ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁵ is H, halogen, CN, or —X—R^(X);-   R^(5′) is H, halogen, CN, or —X—R^(X);-   R⁶ is H, halogen, CN, or —X—R^(X);-   R^(6′) is H, halogen, CN, or —X—R^(X);-   R⁷ is H, halogen, CN, or —X—R^(X);-   X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—; and-   R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to two    non-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced    with —O— and said C₃-C₈ cycloaliphatic is substituted with 0-3    substituents selected from halogen and C₁-C₄ alkyl.

In one embodiment, the invention features a compound of formula I-B andthe attendant definitions, wherein Y is C. In another embodiment, Y isN.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein m is zero. In another embodiment,m is an integer from 1 to 5. In another embodiment, m is 1. In anotherembodiment, m is 2. In another embodiment, m is 3. In anotherembodiment, m is 4. In another embodiment, m is 5.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein W is a bond and R^(W) is halogen,OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. In another embodiment, W is a bondand R^(W) is halogen. In another embodiment, W is a bond and R^(W) isOH. In another embodiment, W is a bond and R^(W) is NH₂. In anotherembodiment, W is a bond and R^(W) is NHR′. In another embodiment, W is abond and R^(W) is CN. In another embodiment, W is a bond and R^(W) isCF₃. In another embodiment, W is a bond and R^(W) is OCF₃.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein W is C₁-C₆ alkyl wherein saidC₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. In another embodiment, Wis CH₃, CH₂CH₃, CH₂CH₂CH₃, or isopropyl. In another embodiment, W isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen,wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O—, —CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. Inanother embodiment, W is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, or O-isopropyl. Inanother embodiment, W is OCH₂CF₃, OCH₂CH₂CH₂CF₃, or OCHF₂. In anotherembodiment, W is OCH₂CH₂OCH₃, CH₂OH, OC(CH₃)₃, or CH₂CH₂OCH₃.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein W is C₁-C₆ alkyl wherein saidC₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂,CN, CF₃, or OCF₃. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or—SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO—, or —SO₂—, and R^(W) is H, OH, NH₂, or NHR′. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H. In another embodiment, W is C₁ alkylwherein one CH₂ unit of said C₁ alkyl is replaced with —CO— and R^(W) isOH. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁alkyl is replaced with —CO— and R^(W) is NH₂. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—and R^(W) is NHR′. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is H, OH, NH₂, orNHR′. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of saidC₁ alkyl is replaced with —SO₂— and R^(W) is H. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —SO₂—and R^(W) is OH. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is NH₂. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —SO₂— and R^(W) is NHR′.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein W is C₁-C₆ alkyl wherein saidC₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) absent. In another embodiment, W isC₂ alkyl wherein one CH₂ unit of said C₂ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is absent. In another embodiment, Wis C₂ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—,or —SO₂—, and R^(W) is absent.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein W is a bond and R^(W) is a 3-6membered saturated, partially unsaturated, or fully unsaturatedmonocyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In another embodiment, W is a bond andR^(W) is a 5-membered aromatic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In another embodiment, W is abond and R^(W) is a 5-membered aromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In anotherembodiment, W is a bond and R^(W) is pyrrolyl, pyrazolyl, thiazolyl,thiadiazolyl, imidazolyl, oxazolyl, triazolyl, or tetrazolyl.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein ring A₁ is selected from:

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein R¹ is H. In another embodiment,R¹ is halogen. In another embodiment, R¹ is CN. In another embodiment,R¹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen. In another embodiment, R¹ is CF₃.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein R² is H. In another embodiment,R² is halogen. In another embodiment, R² is Cl. In another embodiment,R² is F. In another embodiment, R² is CN. In another embodiment, R² isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R² is CF₃. In another embodiment, R² is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen wherein one CH₂unit of said C₁-C₆ alkyl is replaced with —O—. In another embodiment, R²is OCF₃. In another embodiment, R² is F, Cl, CN, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein R³ is H. In another embodiment,R³ is halogen. In another embodiment, R³ is Cl. In another embodiment,R³ is F. In another embodiment, R³ is CN. In another embodiment, R³ isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R³ is t-butyl. In another embodiment, R³ is CF₃. Inanother embodiment, R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein R⁴ is H. In another embodiment,R⁴ is halogen. In another embodiment, R⁴ is CN. In another embodiment,R⁴ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen. In another embodiment, R⁴ is CF₃.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein R¹, R², R³, and R⁴ is H.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein R⁵ is H. In another embodiment,R⁵ is halogen. In another embodiment, R⁵ is Cl. In another embodiment,R⁵ is F. In another embodiment, R⁵ is CN. In another embodiment, R⁵ is—X—R^(X). In another embodiment, R⁵ is —X—R^(X) wherein R^(X) is absent.In another embodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R⁵ is CH₃. In another embodiment, R⁵ is —X—R^(X)wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁵ is OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, or OCH(CH₃)₂. In another embodiment, R⁵ is OCH₃. In anotherembodiment, R⁵ is CH₂OH. In another embodiment, R⁵ is OCF₃. In anotherembodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein R^(5′) is H. In anotherembodiment, R^(5′) is halogen. In another embodiment, R^(5′) is Cl. Inanother embodiment, R^(5′) is F. In another embodiment, R^(5′) is CN. Inanother embodiment, R^(5′) is —X—R^(X). In another embodiment, R^(5′) is—X—R^(X) wherein R^(X) is absent. In another embodiment, R^(5′) is—X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆alkyl is substituted with 0-6 halogen. In another embodiment, R^(5′) isCH₃. In another embodiment, R^(5′) is —X—R^(X) wherein R^(X) is absentand X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O—.In another embodiment, R^(5′) is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, orOCH(CH₃)₂. In another embodiment, R^(5′) is OCH₃. In another embodiment,R^(5′) is CH₂OH. In another embodiment, R^(5′) is OCF₃. In anotherembodiment, R^(5′) is OCHF₂.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, R⁶ is H. In another embodiment, R⁶ ishalogen. In another embodiment, R⁶ is Cl. In another embodiment, R⁶ isF. In another embodiment, R⁶ is CN. In another embodiment, R⁶ is—X—R^(X). In another embodiment, R⁶ is —X—R^(X) wherein R^(X) is absent.In another embodiment, R⁶ is —X—R^(X) wherein R^(X) is absent and X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R⁶ is CH₃. In another embodiment, R⁶ is —X—R^(X)wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁶ is OCH₃.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein R^(6′) is H. In anotherembodiment, R^(6′) is halogen. In another embodiment, R^(6′) is Cl. Inanother embodiment, R^(6′) is F. In another embodiment, R^(6′) is CN. Inanother embodiment, R^(6′) is —X—R^(X). In another embodiment, R^(6′) is—X—R^(X) wherein R^(X) is absent. In another embodiment, R^(6′) is—X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆alkyl is substituted with 0-6 halogen. In another embodiment, R^(6′) isCH₃. In another embodiment, R^(6′) is —X—R^(X) wherein R^(X) is absentand X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O—.In another embodiment, R^(6′) is OCH₃.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein R⁷ is H. In another embodiment,R⁷ is halogen. In another embodiment, R⁷ is Cl. In another embodiment,R⁷ is F. In another embodiment, R⁷ is CN. In another embodiment, R⁷ is—X—R^(X). In another embodiment, R⁷ is —X—R^(X) wherein R^(X) is absent.In another embodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. Inanother embodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X)wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formula I-Bwherein R⁷ is —X—R^(X) wherein X is a bond and R^(X) is C₃-C₈cycloaliphatic and said C₃-C₈ cycloaliphatic is substituted with 0-3substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is a bond and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein R⁷ is —X—R^(X) wherein X is C₁-C₆alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen whereinone CH₂ unit of said C₁-C₆ alkyl is replaced with —O— and R^(X) is C₃-C₈cycloaliphatic and said C₃-C₈ cycloaliphatic is substituted with up 0-3substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is OCH₂ and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein ring A is selected from:

In another aspect, the invention provides a compound of formula I-B-1:

-   or a pharmaceutically acceptable salt thereof,-   wherein, independently for each occurrence:-   Y is C or N;-   m is an integer from 0 to 5 inclusive;-   W is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or —SO₂—;-   R^(W) is absent, H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, OCF₃, or a    3-6 membered saturated, partially unsaturated, or fully unsaturated    monocyclic ring having 0-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   R′ is C₁-C₆ alkyl;-   R¹ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen and wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R² is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R³ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁴ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁵ is halogen, CN, or —X—R^(X);-   X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—; and-   R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to two    non-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced    with —O— and said C₃-C₈ cycloaliphatic is substituted with 0-3    substituents selected from halogen and C₁-C₄ alkyl.

In one embodiment, the invention features a compound of formula I-B-1and the attendant definitions, wherein Y is C. In another embodiment, Yis N.

In another embodiment, the invention features a compound of formulaI-B-1 and the attendant definitions, wherein m is zero. In anotherembodiment, m is an integer from 1 to 5. In another embodiment, m is 1.In another embodiment, m is 2. In another embodiment, m is 3. In anotherembodiment, m is 4. In another embodiment, m is 5.

In another embodiment, the invention features a compound of formulaI-B-1 and the attendant definitions, wherein W is a bond and R^(W) ishalogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. In another embodiment, Wis a bond and R^(W) is halogen. In another embodiment, W is a bond andR^(W) is OH. In another embodiment, W is a bond and R^(W) is NH₂. Inanother embodiment, W is a bond and R^(W) is NHR′. In anotherembodiment, W is a bond and R^(W) is CN. In another embodiment, W is abond and R^(W) is CF₃. In another embodiment, W is a bond and R^(W) isOCF₃.

In another embodiment, the invention features a compound of formulaI-B-1 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. In another embodiment, Wis CH₃, CH₂CH₃, CH₂CH₂CH₃, or isopropyl. In another embodiment, W isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen,wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O—, —CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. Inanother embodiment, W is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, or O-isopropyl. Inanother embodiment, W is OCH₂CF₃, OCH₂CH₂CH₂CF₃, or OCHF₂. In anotherembodiment, W is OCH₂CH₂OCH₃, CH₂OH, OC(CH₃)₃, or CH₂CH₂OCH₃.

In another embodiment, the invention features a compound of formulaI-B-1 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂,CN, CF₃, or OCF₃. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or—SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO—, or —SO₂—, and R^(W) is H, OH, NH₂, or NHR′. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H. In another embodiment, W is C₁ alkylwherein one CH₂ unit of said C₁ alkyl is replaced with —CO— and R^(W) isOH. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁alkyl is replaced with —CO— and R^(W) is NH₂. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—and R^(W) is NHR′. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is H, OH, NH₂, orNHR′. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of saidC₁ alkyl is replaced with —SO₂— and R^(W) is H. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —SO₂—and R^(W) is OH. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is NH₂. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —SO₂— and R^(W) is NHR′.

In another embodiment, the invention features a compound of formulaI-B-1 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) absent. In another embodiment, W isC₂ alkyl wherein one CH₂ unit of said C₂ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is absent. In another embodiment, Wis C₂ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—,or —SO₂—, and R^(W) is absent.

In another embodiment, the invention features a compound of formulaI-B-1 and the attendant definitions, wherein W is a bond and R^(W) is a3-6 membered saturated, partially unsaturated, or fully unsaturatedmonocyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In another embodiment, W is a bond andR^(W) is a 5-membered aromatic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In another embodiment, W is abond and R^(W) is a 5-membered aromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In anotherembodiment, W is a bond and R^(W) is pyrrolyl, pyrazolyl, thiazolyl,thiadiazolyl, imidazolyl, oxazolyl, triazolyl, or tetrazolyl.

In another embodiment, the invention features a compound of formulaI-B-1 and the attendant definitions, wherein ring A₁ is selected from:

In another embodiment, the invention features a compound of formulaI-B-1 and the attendant definitions, wherein R¹ is H. In anotherembodiment, R¹ is halogen. In another embodiment, R¹ is CN. In anotherembodiment, R¹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R¹ is CF₃.

In another embodiment, the invention features a compound of formulaI-B-1 and the attendant definitions, wherein R² is H. In anotherembodiment, R² is halogen. In another embodiment, R² is Cl. In anotherembodiment, R² is F. In another embodiment, R² is CN. In anotherembodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R² is CF₃. In anotherembodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replacedwith —O—. In another embodiment, R² is OCF₃. In another embodiment, R²is F, Cl, CN, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formulaI-B-1 and the attendant definitions, wherein R³ is H. In anotherembodiment, R³ is halogen. In another embodiment, R³ is Cl. In anotherembodiment, R³ is F. In another embodiment, R³ is CN. In anotherembodiment, R³ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R³ is t-butyl. In anotherembodiment, R³ is CF₃. In another embodiment, R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formulaI-B-1 and the attendant definitions, wherein R⁴ is H. In anotherembodiment, R⁴ is halogen. In another embodiment, R⁴ is CN. In anotherembodiment, R⁴ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R⁴ is CF₃.

In another embodiment, the invention features a compound of formulaI-B-1 and the attendant definitions, wherein R¹, R², R³, and R⁴ is H.

In another embodiment, the invention features a compound of formulaI-B-1 and the attendant definitions, wherein R⁵ is halogen. In anotherembodiment, R⁵ is Cl. In another embodiment, R⁵ is F. In anotherembodiment, R⁵ is CN. In another embodiment, R⁵ is —X—R^(X). In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁵ is CH₃. In another embodiment, R⁵ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁵ is OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, or OCH(CH₃)₂. In another embodiment, R⁵ is OCH₃. In anotherembodiment, R⁵ is CH₂OH. In another embodiment, R⁵ is OCF₃. In anotherembodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formulaI-B-1 and the attendant definitions, wherein ring A is selected from:

In another aspect, the invention provides a compound of formula I-B-2:

-   or a pharmaceutically acceptable salt thereof,-   wherein, independently for each occurrence:-   Y is C or N;-   m is an integer from 0 to 5 inclusive;-   W is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or —SO₂—;-   R^(W) is absent, H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, OCF₃, or a    3-6 membered saturated, partially unsaturated, or fully unsaturated    monocyclic ring having 0-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   R′ is C₁-C₆ alkyl;-   R¹ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen and wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R² is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R³ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁴ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁷ is halogen, CN, or —X—R^(X);-   X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—; and-   R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to two    non-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced    with —O— and said C₃-C₈ cycloaliphatic is substituted with 0-3    substituents selected from halogen and C₁-C₄ alkyl.

In one embodiment, the invention features a compound of formula I-B-2and the attendant definitions, wherein Y is C. In another embodiment, Yis N.

In another embodiment, the invention features a compound of formulaI-B-2 and the attendant definitions, wherein m is zero. In anotherembodiment, m is an integer from 1 to 5. In another embodiment, m is 1.In another embodiment, m is 2. In another embodiment, m is 3. In anotherembodiment, m is 4. In another embodiment, m is 5.

In another embodiment, the invention features a compound of formulaI-B-2 and the attendant definitions, wherein W is a bond and R^(W) ishalogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. In another embodiment, Wis a bond and R^(W) is halogen. In another embodiment, W is a bond andR^(W) is OH. In another embodiment, W is a bond and R^(W) is NH₂. Inanother embodiment, W is a bond and R^(W) is NHR′. In anotherembodiment, W is a bond and R^(W) is CN. In another embodiment, W is abond and R^(W) is CF₃. In another embodiment, W is a bond and R^(W) isOCF₃.

In another embodiment, the invention features a compound of formulaI-B-2 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. In another embodiment, Wis CH₃, CH₂CH₃, CH₂CH₂CH₃, or isopropyl. In another embodiment, W isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen,wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O—, —CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. Inanother embodiment, W is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, or O-isopropyl. Inanother embodiment, W is OCH₂CF₃, OCH₂CH₂CH₂CF₃, or OCHF₂. In anotherembodiment, W is OCH₂CH₂OCH₃, CH₂OH, OC(CH₃)₃, or CH₂CH₂OCH₃.

In another embodiment, the invention features a compound of formulaI-B-2 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂,CN, CF₃, or OCF₃. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or—SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO—, or —SO₂—, and R^(W) is H, OH, NH₂, or NHR′. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H. In another embodiment, W is C₁ alkylwherein one CH₂ unit of said C₁ alkyl is replaced with —CO— and R^(W) isOH. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁alkyl is replaced with —CO— and R^(W) is NH₂. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—and R^(W) is NHR′. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is H, OH, NH₂, orNHR′. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of saidC₁ alkyl is replaced with —SO₂— and R^(W) is H. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —SO₂—and R^(W) is OH. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is NH₂. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —SO₂— and R^(W) is NHR′.

In another embodiment, the invention features a compound of formulaI-B-2 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O——CO—, —S—, —SO—, or —SO₂—, and R^(W) absent. In another embodiment, W isC₂ alkyl wherein one CH₂ unit of said C₂ alkyl may be replaced with —O——CO—, —S—, —SO—, or —SO₂—, and R^(W) is absent. In another embodiment, Wis C₂ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—,or —SO₂—, and R^(W) is absent.

In another embodiment, the invention features a compound of formulaI-B-2 and the attendant definitions, wherein W is a bond and R^(W) is a3-6 membered saturated, partially unsaturated, or fully unsaturatedmonocyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In another embodiment, W is a bond andR^(W) is a 5-membered aromatic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In another embodiment, W is abond and R^(W) is a 5-membered aromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In anotherembodiment, W is a bond and R^(W) is pyrrolyl, pyrazolyl, thiazolyl,thiadiazolyl, imidazolyl, oxazolyl, triazolyl, or tetrazolyl.

In another embodiment, the invention features a compound of formulaI-B-2 and the attendant definitions, wherein ring A₁ is selected from:

In another embodiment, the invention features a compound of formulaI-B-2 and the attendant definitions, wherein R¹ is H. In anotherembodiment, R¹ is halogen. In another embodiment, R¹ is CN. In anotherembodiment, R¹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R¹ is CF₃.

In another embodiment, the invention features a compound of formulaI-B-2 and the attendant definitions, wherein R² is H. In anotherembodiment, R² is halogen. In another embodiment, R² is Cl. In anotherembodiment, R² is F. In another embodiment, R² is CN. In anotherembodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R² is CF₃. In anotherembodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replacedwith —O—. In another embodiment, R² is OCF₃. In another embodiment, R²is F, Cl, CN, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formulaI-B-2 and the attendant definitions, wherein R³ is H. In anotherembodiment, R³ is halogen. In another embodiment, R³ is Cl. In anotherembodiment, R³ is F. In another embodiment, R³ is CN. In anotherembodiment, R³ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R³ is t-butyl. In anotherembodiment, R³ is CF₃. In another embodiment, R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formulaI-B-2 and the attendant definitions, wherein R⁴ is H. In anotherembodiment, R⁴ is halogen. In another embodiment, R⁴ is CN. In anotherembodiment, R⁴ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R⁴ is CF₃.

In another embodiment, the invention features a compound of formulaI-B-2 and the attendant definitions, wherein R¹, R², R³, and R⁴ is H.

In another embodiment, the invention features a compound of formulaI-B-2 and the attendant definitions, wherein R⁷ is halogen. In anotherembodiment, R⁷ is Cl. In another embodiment, R⁷ is F. In anotherembodiment, R⁷ is CN. In another embodiment, R⁷ is —X—R^(X). In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. In anotherembodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formulaI-B-2 wherein R⁷ is —X—R^(X) wherein X is a bond and R^(X) is C₃-C₈cycloaliphatic and said C₃-C₈ cycloaliphatic is substituted with 0-3substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is a bond and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formulaI-B-2 and the attendant definitions, wherein R⁷ is —X—R^(X) wherein X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O— and R^(X)is C₃-C₈ cycloaliphatic and said C₃-C₈ cycloaliphatic is substitutedwith up 0-3 substituents selected from halogen and C₁-C₄ alkyl. Inanother embodiment, R⁷ is —X—R^(X) wherein X is OCH₂ and R^(X) iscyclopropyl.

In another embodiment, the invention features a compound of formulaI-B-2 and the attendant definitions, wherein ring A is selected from:

In another aspect, the invention provides a compound of formula I-B-3:

-   or a pharmaceutically acceptable salt thereof,-   wherein, independently for each occurrence:-   Y is C or N;-   m is an integer from 0 to 5 inclusive;-   W is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or —SO₂—;-   R^(W) is absent, H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, OCF₃, or a    3-6 membered saturated, partially unsaturated, or fully unsaturated    monocyclic ring having 0-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   R′ is C₁-C₆ alkyl;-   R¹ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen and wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R² is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R³ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁴ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁶ is halogen, CN, or —X—R^(X);-   R⁷ is halogen, CN, or —X—R^(X);-   X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—; and-   R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to two    non-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced    with —O— and said C₃-C₈ cycloaliphatic is substituted with 0-3    substituents selected from halogen and C₁-C₄ alkyl.

In one embodiment, the invention features a compound of formula I-B-3and the attendant definitions, wherein Y is C. In another embodiment, Yis N.

In another embodiment, the invention features a compound of formulaI-B-3 and the attendant definitions, wherein m is zero. In anotherembodiment, m is an integer from 1 to 5. In another embodiment, m is 1.In another embodiment, m is 2. In another embodiment, m is 3. In anotherembodiment, m is 4. In another embodiment, m is 5.

In another embodiment, the invention features a compound of formulaI-B-3 and the attendant definitions, wherein W is a bond and R^(W) ishalogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. In another embodiment, Wis a bond and R^(W) is halogen. In another embodiment, W is a bond andR^(W) is OH. In another embodiment, W is a bond and R^(W) is NH₂. Inanother embodiment, W is a bond and R^(W) is NHR′. In anotherembodiment, W is a bond and R^(W) is CN. In another embodiment, W is abond and R^(W) is CF₃. In another embodiment, W is a bond and R^(W) isOCF₃.

In another embodiment, the invention features a compound of formulaI-B-3 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. In another embodiment, Wis CH₃, CH₂CH₃, CH₂CH₂CH₃, or isopropyl. In another embodiment, W isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen,wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O—, —CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. Inanother embodiment, W is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, or O-isopropyl. Inanother embodiment, W is OCH₂CF₃, OCH₂CH₂CH₂CF₃, or OCHF₂. In anotherembodiment, W is OCH₂CH₂OCH₃, CH₂OH, OC(CH₃)₃, or CH₂CH₂OCH₃.

In another embodiment, the invention features a compound of formulaI-B-3 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂,CN, CF₃, or OCF₃. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or—SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO—, or —SO₂—, and R^(W) is H, OH, NH₂, or NHR′. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H. In another embodiment, W is C₁ alkylwherein one CH₂ unit of said C₁ alkyl is replaced with —CO— and R^(W) isOH. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁alkyl is replaced with —CO— and R^(W) is NH₂. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—and R^(W) is NHR′. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is H, OH, NH₂, orNHR′. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of saidC₁ alkyl is replaced with —SO₂— and R^(W) is H. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —SO₂—and R^(W) is OH. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is NH₂. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —SO₂— and R^(W) is NHR′.

In another embodiment, the invention features a compound of formulaI-B-3 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) absent. In another embodiment, W isC₂ alkyl wherein one CH₂ unit of said C₂ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is absent. In another embodiment, Wis C₂ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—,or —SO₂—, and R^(W) is absent.

In another embodiment, the invention features a compound of formulaI-B-3 and the attendant definitions, wherein W is a bond and R^(W) is a3-6 membered saturated, partially unsaturated, or fully unsaturatedmonocyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In another embodiment, W is a bond andR^(W) is a 5-membered aromatic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In another embodiment, W is abond and R^(W) is a 5-membered aromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In anotherembodiment, W is a bond and R^(W) is pyrrolyl, pyrazolyl, thiazolyl,thiadiazolyl, imidazolyl, oxazolyl, triazolyl, or tetrazolyl.

In another embodiment, the invention features a compound of formulaI-B-3 and the attendant definitions, wherein ring A₁ is selected from:

In another embodiment, the invention features a compound of formulaI-B-3 and the attendant definitions, wherein R¹ is H. In anotherembodiment, R¹ is halogen. In another embodiment, R¹ is CN. In anotherembodiment, R¹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R¹ is CF₃.

In another embodiment, the invention features a compound of formulaI-B-3 and the attendant definitions, wherein R² is H. In anotherembodiment, R² is halogen. In another embodiment, R² is Cl. In anotherembodiment, R² is F. In another embodiment, R² is CN. In anotherembodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R² is CF₃. In anotherembodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replacedwith —O—. In another embodiment, R² is OCF₃. In another embodiment, R²is F, Cl, CN, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formulaI-B-3 and the attendant definitions, wherein R³ is H. In anotherembodiment, R³ is halogen. In another embodiment, R³ is Cl. In anotherembodiment, R³ is F. In another embodiment, R³ is CN. In anotherembodiment, R³ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R³ is t-butyl. In anotherembodiment, R³ is CF₃. In another embodiment, R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formulaI-B-3 and the attendant definitions, wherein R⁴ is H. In anotherembodiment, R⁴ is halogen. In another embodiment, R⁴ is CN. In anotherembodiment, R⁴ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R⁴ is CF₃.

In another embodiment, the invention features a compound of formulaI-B-3 and the attendant definitions, wherein R¹, R², R³, and R⁴ is H.

In another embodiment, the invention features a compound of formulaI-B-3 and the attendant definitions, R⁶ is halogen. In anotherembodiment, R⁶ is Cl. In another embodiment, R⁶ is F. In anotherembodiment, R⁶ is CN. In another embodiment, R⁶ is —X—R^(X). In anotherembodiment, R⁶ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁶ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁶ is CH₃. In another embodiment, R⁶ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁶ is OCH₃.

In another embodiment, the invention features a compound of formulaI-B-3 and the attendant definitions, wherein R⁷ is halogen. In anotherembodiment, R⁷ is Cl. In another embodiment, R⁷ is F. In anotherembodiment, R⁷ is CN. In another embodiment, R⁷ is —X—R^(X). In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. In anotherembodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formulaI-B-3 wherein R⁷ is —X—R^(X) wherein X is a bond and R^(X) is C₃-C₈cycloaliphatic and said C₃-C₈ cycloaliphatic is substituted with 0-3substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is a bond and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formulaI-B-3 and the attendant definitions, wherein R⁷ is —X—R^(X) wherein X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O— and R^(X)is C₃-C₈ cycloaliphatic and said C₃-C₈ cycloaliphatic is substitutedwith up 0-3 substituents selected from halogen and C₁-C₄ alkyl. Inanother embodiment, R⁷ is —X—R^(X) wherein X is OCH₂ and R^(X) iscyclopropyl.

In another embodiment, the invention features a compound of formulaI-B-3 and the attendant definitions, wherein ring A is selected from:

In another aspect, the invention provides a compound of formula I-B-4:

-   or a pharmaceutically acceptable salt thereof,-   wherein, independently for each occurrence:-   Y is C or N;-   m is an integer from 0 to 5 inclusive;-   W is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or —SO₂—;-   R^(W) is absent, H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, OCF₃, or a    3-6 membered saturated, partially unsaturated, or fully unsaturated    monocyclic ring having 0-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   R′ is C₁-C₆ alkyl;-   R¹ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen and wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R² is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R³ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁴ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁵ is halogen, CN, or —X—R^(X);-   R⁷ is halogen, CN, or —X—R^(X);-   X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—; and-   R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to two    non-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced    with —O— and said C₃-C₈ cycloaliphatic is substituted with 0-3    substituents selected from halogen and C₁-C₄ alkyl.

In one embodiment, the invention features a compound of formula I-B-4and the attendant definitions, wherein Y is C. In another embodiment, Yis N.

In another embodiment, the invention features a compound of formulaI-B-4 and the attendant definitions, wherein m is zero. In anotherembodiment, m is an integer from 1 to 5. In another embodiment, m is 1.In another embodiment, m is 2. In another embodiment, m is 3. In anotherembodiment, m is 4. In another embodiment, m is 5.

In another embodiment, the invention features a compound of formulaI-B-4 and the attendant definitions, wherein W is a bond and R^(W) ishalogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. In another embodiment, Wis a bond and R^(W) is halogen. In another embodiment, W is a bond andR^(W) is OH. In another embodiment, W is a bond and R^(W) is NH₂. Inanother embodiment, W is a bond and R^(W) is NHR′. In anotherembodiment, W is a bond and R^(W) is CN. In another embodiment, W is abond and R^(W) is CF₃. In another embodiment, W is a bond and R^(W) isOCF₃.

In another embodiment, the invention features a compound of formulaI-B-4 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. In another embodiment, Wis CH₃, CH₂CH₃, CH₂CH₂CH₃, or isopropyl. In another embodiment, W isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen,wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O—, —CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. Inanother embodiment, W is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, or O-isopropyl. Inanother embodiment, W is OCH₂CF₃, OCH₂CH₂CH₂CF₃, or OCHF₂. In anotherembodiment, W is OCH₂CH₂OCH₃, CH₂OH, OC(CH₃)₃, or CH₂CH₂OCH₃.

In another embodiment, the invention features a compound of formulaI-B-4 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂,CN, CF₃, or OCF₃. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or—SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO—, or —SO₂—, and R^(W) is H, OH, NH₂, or NHR′. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H. In another embodiment, W is C₁ alkylwherein one CH₂ unit of said C₁ alkyl is replaced with —CO— and R^(W) isOH. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁alkyl is replaced with —CO— and R^(W) is NH₂. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—and R^(W) is NHR′. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is H, OH, NH₂, orNHR′. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of saidC₁ alkyl is replaced with —SO₂— and R^(W) is H. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —SO₂—and R^(W) is OH. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is NH₂. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —SO₂— and R^(W) is NHR′.

In another embodiment, the invention features a compound of formulaI-B-4 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) absent. In another embodiment, W isC₂ alkyl wherein one CH₂ unit of said C₂ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is absent. In another embodiment, Wis C₂ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—,or —SO₂—, and R^(W) is absent.

In another embodiment, the invention features a compound of formulaI-B-4 and the attendant definitions, wherein W is a bond and R^(W) is a3-6 membered saturated, partially unsaturated, or fully unsaturatedmonocyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In another embodiment, W is a bond andR^(W) is a 5-membered aromatic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In another embodiment, W is abond and R^(W) is a 5-membered aromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In anotherembodiment, W is a bond and R^(W) is pyrrolyl, pyrazolyl, thiazolyl,thiadiazolyl, imidazolyl, oxazolyl, triazolyl, or tetrazolyl.

In another embodiment, the invention features a compound of formulaI-B-4 and the attendant definitions, wherein ring A₁ is selected from:

In another embodiment, the invention features a compound of formulaI-B-4 and the attendant definitions, wherein R¹ is H. In anotherembodiment, R¹ is halogen. In another embodiment, R¹ is CN. In anotherembodiment, R¹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R¹ is CF₃.

In another embodiment, the invention features a compound of formulaI-B-4 and the attendant definitions, wherein R² is H. In anotherembodiment, R² is halogen. In another embodiment, R² is Cl. In anotherembodiment, R² is F. In another embodiment, R² is CN. In anotherembodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R² is CF₃. In anotherembodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replacedwith —O—. In another embodiment, R² is OCF₃. In another embodiment, R²is F, Cl, CN, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formulaI-B-4 and the attendant definitions, wherein R³ is H. In anotherembodiment, R³ is halogen. In another embodiment, R³ is Cl. In anotherembodiment, R³ is F. In another embodiment, R³ is CN. In anotherembodiment, R³ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R³ is t-butyl. In anotherembodiment, R³ is CF₃. In another embodiment, R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formulaI-B-4 and the attendant definitions, wherein R⁴ is H. In anotherembodiment, R⁴ is halogen. In another embodiment, R⁴ is CN. In anotherembodiment, R⁴ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R⁴ is CF₃.

In another embodiment, the invention features a compound of formulaI-B-4 and the attendant definitions, wherein R¹, R², R³, and R⁴ is H.

In another embodiment, the invention features a compound of formulaI-B-4 and the attendant definitions, wherein R⁵ is halogen. In anotherembodiment, R⁵ is Cl. In another embodiment, R⁵ is F. In anotherembodiment, R⁵ is CN. In another embodiment, R⁵ is —X—R^(X). In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁵ is CH₃. In another embodiment, R⁵ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁵ is OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, or OCH(CH₃)₂. In another embodiment, R⁵ is OCH₃. In anotherembodiment, R⁵ is CH₂OH. In another embodiment, R⁵ is OCF₃. In anotherembodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formulaI-B-4 and the attendant definitions, wherein R⁷ is halogen. In anotherembodiment, R⁷ is Cl. In another embodiment, R⁷ is F. In anotherembodiment, R⁷ is CN. In another embodiment, R⁷ is —X—R^(X). In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. In anotherembodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formulaI-B-4 wherein R⁷ is —X—R^(X) wherein X is a bond and R^(X) is C₃-C₈cycloaliphatic and said C₃-C₈ cycloaliphatic is substituted with 0-3substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is a bond and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formulaI-B-4 and the attendant definitions, wherein R⁷ is —X—R^(X) wherein X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O— and R^(X)is C₃-C₈ cycloaliphatic and said C₃-C₈ cycloaliphatic is substitutedwith up 0-3 substituents selected from halogen and C₁-C₄ alkyl. Inanother embodiment, R⁷ is —X—R^(X) wherein X is OCH₂ and R^(X) iscyclopropyl.

In another embodiment, the invention features a compound of formulaI-B-4 and the attendant definitions, wherein ring A is selected from:

In another aspect, the invention provides a compound of formula I-C:

-   or a pharmaceutically acceptable salt thereof,-   wherein, independently for each occurrence:-   Y is C or N;-   m is an integer from 0 to 5 inclusive;-   W is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or —SO₂—;-   R^(W) is absent, H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, OCF₃, or a    3-6 membered saturated, partially unsaturated, or fully unsaturated    monocyclic ring having 0-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   R′ is C₁-C₆ alkyl;-   R¹ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen and wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R² is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R³ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁴ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁵ is H, halogen, CN, or —X—R^(X);-   R^(5′) is H, halogen, CN, or —X—R^(X);-   R⁶ is H, halogen, CN, or —X—R^(X);-   R^(6′) is H, halogen, CN, or —X—R^(X);-   R⁷ is H, halogen, CN, or —X—R^(X);-   X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—; and-   R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to two    non-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced    with —O— and said C₃-C₈ cycloaliphatic is substituted with 0-3    substituents selected from halogen and C₁-C₄ alkyl.

In one embodiment, the invention features a compound of formula I-C andthe attendant definitions, wherein Y is C. In another embodiment, Y isN.

In another embodiment, the invention features a compound of formula I-Cand the attendant definitions, wherein m is zero. In another embodiment,m is an integer from 1 to 5. In another embodiment, m is 1. In anotherembodiment, m is 2. In another embodiment, m is 3. In anotherembodiment, m is 4. In another embodiment, m is 5.

In another embodiment, the invention features a compound of formula I-Cand the attendant definitions, wherein W is a bond and R^(W) is halogen,OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. In another embodiment, W is a bondand R^(W) is halogen. In another embodiment, W is a bond and R^(W) isOH. In another embodiment, W is a bond and R^(W) is NH₂. In anotherembodiment, W is a bond and R^(W) is NHR′. In another embodiment, W is abond and R^(W) is CN. In another embodiment, W is a bond and R^(W) isCF₃. In another embodiment, W is a bond and R^(W) is OCF₃.

In another embodiment, the invention features a compound of formula I-Cand the attendant definitions, wherein W is C₁-C₆ alkyl wherein saidC₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. In another embodiment, Wis CH₃, CH₂CH₃, CH₂CH₂CH₃, or isopropyl. In another embodiment, W isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen,wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O—, —CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. Inanother embodiment, W is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, or O-isopropyl. Inanother embodiment, W is OCH₂CF₃, OCH₂CH₂CH₂CF₃, or OCHF₂. In anotherembodiment, W is OCH₂CH₂OCH₃, CH₂OH, OC(CH₃)₃, or CH₂CH₂OCH₃.

In another embodiment, the invention features a compound of formula I-Cand the attendant definitions, wherein W is C₁-C₆ alkyl wherein saidC₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂,CN, CF₃, or OCF₃. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl may be replaced with —O—, —CO—, —S—, —SO—, —SO₂—,and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO—, or —SO₂—, and R^(W) is H, OH, NH₂, or NHR′. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H. In another embodiment, W is C₁ alkylwherein one CH₂ unit of said C₁ alkyl is replaced with —CO— and R^(W) isOH. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁alkyl is replaced with —CO— and R^(W) is NH₂. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—and R^(W) is NHR′. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is H, OH, NH₂, orNHR′. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of saidC₁ alkyl is replaced with —SO₂— and R^(W) is H. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —SO₂—and R^(W) is OH. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is NH₂. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —SO₂— and R^(W) is NHR′.

In another embodiment, the invention features a compound of formula I-Cand the attendant definitions, wherein W is C₁-C₆ alkyl wherein saidC₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) absent. In another embodiment, W isC₂ alkyl wherein one CH₂ unit of said C₂ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is absent. In another embodiment, Wis C₂ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—,or —SO₂—, and R^(W) is absent.

In another embodiment, the invention features a compound of formula I-Cand the attendant definitions, wherein W is a bond and R^(W) is a 3-6membered saturated, partially unsaturated, or fully unsaturatedmonocyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In another embodiment, W is a bond andR^(W) is a 5-membered aromatic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In another embodiment, W is abond and R^(W) is a 5-membered aromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In anotherembodiment, W is a bond and R^(W) is pyrrolyl, pyrazolyl, thiazolyl,thiadiazolyl, imidazolyl, oxazolyl, triazolyl, or tetrazolyl.

In another embodiment, the invention features a compound of formula I-Cand the attendant definitions, wherein ring A₁ is selected from:

In another embodiment, the invention features a compound of formula I-Cand the attendant definitions, wherein R¹ is H. In another embodiment,R¹ is halogen. In another embodiment, R¹ is CN. In another embodiment,R¹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen. In another embodiment, R¹ is CF₃.

In another embodiment, the invention features a compound of formula I-Cand the attendant definitions, wherein R² is H. In another embodiment,R² is halogen. In another embodiment, R² is Cl. In another embodiment,R² is F. In another embodiment, R² is CN. In another embodiment, R² isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R² is CF₃. In another embodiment, R² is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen wherein one CH₂unit of said C₁-C₆ alkyl is replaced with —O—. In another embodiment, R²is OCF₃. In another embodiment, R² is F, Cl, CN, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formula I-Cand the attendant definitions, wherein R³ is H. In another embodiment,R³ is halogen. In another embodiment, R³ is Cl. In another embodiment,R³ is F. In another embodiment, R³ is CN. In another embodiment, R³ isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R³ is t-butyl. In another embodiment, R³ is CF₃. Inanother embodiment, R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formula I-Cand the attendant definitions, wherein R⁴ is H. In another embodiment,R⁴ is halogen. In another embodiment, R⁴ is CN. In another embodiment,R⁴ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen. In another embodiment, R⁴ is CF₃.

In another embodiment, the invention features a compound of formula I-Cand the attendant definitions, wherein R¹, R², R³, and R⁴ is H.

In another embodiment, the invention features a compound of formula I-Cand the attendant definitions, wherein R⁵ is H. In another embodiment,R⁵ is halogen. In another embodiment, R⁵ is Cl. In another embodiment,R⁵ is F. In another embodiment, R⁵ is CN. In another embodiment, R⁵ is—X—R^(X). In another embodiment, R⁵ is —X—R^(X) wherein R^(X) is absent.In another embodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R⁵ is CH₃. In another embodiment, R⁵ is —X—R^(X)wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁵ is OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, or OCH(CH₃)₂. In another embodiment, R⁵ is OCH₃. In anotherembodiment, R⁵ is CH₂OH. In another embodiment, R⁵ is OCF₃. In anotherembodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula I-Cand the attendant definitions, wherein R^(5′) is H. In anotherembodiment, R^(5′) is halogen. In another embodiment, R^(5′) is Cl. Inanother embodiment, R^(5′) is F. In another embodiment, R^(5′) is CN. Inanother embodiment, R^(5′) is —X—R^(X). In another embodiment, R^(5′) is—X—R^(X) wherein R^(X) is absent. In another embodiment, R^(5′) is—X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆alkyl is substituted with 0-6 halogen. In another embodiment, R^(5′) isCH₃. In another embodiment, R^(5′) is —X—R^(X) wherein R^(X) is absentand X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O—.In another embodiment, R^(5′) is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, orOCH(CH₃)₂. In another embodiment, R^(5′) is OCH₃. In another embodiment,R^(5′) is CH₂OH. In another embodiment, R^(5′) is OCF₃. In anotherembodiment, R^(5′) is OCHF₂.

In another embodiment, the invention features a compound of formula I-Cand the attendant definitions, R⁶ is H. In another embodiment, R⁶ ishalogen. In another embodiment, R⁶ is Cl. In another embodiment, R⁶ isF. In another embodiment, R⁶ is CN. In another embodiment, R⁶ is—X—R^(X). In another embodiment, R⁶ is —X—R^(X) wherein R^(X) is absent.In another embodiment, R⁶ is —X—R^(X) wherein R^(X) is absent and X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R⁶ is CH₃. In another embodiment, R⁶ is —X—R^(X)wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁶ is OCH₃.

In another embodiment, the invention features a compound of formula I-Cand the attendant definitions, wherein R^(6′) is H. In anotherembodiment, R^(6′) is halogen. In another embodiment, R^(6′) is Cl. Inanother embodiment, R^(6′) is F. In another embodiment, R^(6′) is CN. Inanother embodiment, R^(6′) is —X—R^(X). In another embodiment, R^(6′) is—X—R^(X) wherein R^(X) is absent. In another embodiment, R^(6′) is—X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆alkyl is substituted with 0-6 halogen. In another embodiment, R^(6′) isCH₃. In another embodiment, R^(6′) is —X—R^(X) wherein R^(X) is absentand X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O—.In another embodiment, R^(6′) is OCH₃.

In another embodiment, the invention features a compound of formula I-Cand the attendant definitions, wherein R⁷ is H. In another embodiment,R⁷ is halogen. In another embodiment, R⁷ is Cl. In another embodiment,R⁷ is F. In another embodiment, R⁷ is CN. In another embodiment, R⁷ is—X—R^(X). In another embodiment, R⁷ is —X—R^(X) wherein R^(X) is absent.In another embodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. Inanother embodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X)wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formula I-Cwherein R⁷ is —X—R^(X) wherein X is a bond and R^(X) is C₃-C₈cycloaliphatic and said C₃-C₈ cycloaliphatic is substituted with 0-3substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is a bond and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Cand the attendant definitions, wherein R⁷ is —X—R^(X) wherein X is C₁-C₆alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen whereinone CH₂ unit of said C₁-C₆ alkyl is replaced with —O— and R^(X) is C₃-C₈cycloaliphatic and said C₃-C₈ cycloaliphatic is substituted with up 0-3substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is OCH₂ and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Cand the attendant definitions, wherein ring A is selected from:

In another aspect, the invention provides a compound of formula I-C-1:

-   or a pharmaceutically acceptable salt thereof,-   wherein, independently for each occurrence:-   Y is C or N;-   m is an integer from 0 to 5 inclusive;-   W is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or —SO₂—;-   R^(W) is absent, H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, OCF₃, or a    3-6 membered saturated, partially unsaturated, or fully unsaturated    monocyclic ring having 0-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   R′ is C₁-C₆ alkyl;-   R¹ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen and wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R² is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R³ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁴ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁵ is halogen, CN, or —X—R^(X);-   X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—; and-   R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to two    non-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced    with —O— and said C₃-C₈ cycloaliphatic is substituted with 0-3    substituents selected from halogen and C₁-C₄ alkyl.

In one embodiment, the invention features a compound of formula I-C-1and the attendant definitions, wherein Y is C. In another embodiment, Yis N.

In another embodiment, the invention features a compound of formulaI-C-1 and the attendant definitions, wherein m is zero. In anotherembodiment, m is an integer from 1 to 5. In another embodiment, m is 1.In another embodiment, m is 2. In another embodiment, m is 3. In anotherembodiment, m is 4. In another embodiment, m is 5.

In another embodiment, the invention features a compound of formulaI-C-1 and the attendant definitions, wherein W is a bond and R^(W) ishalogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. In another embodiment, Wis a bond and R^(W) is halogen. In another embodiment, W is a bond andR^(W) is OH. In another embodiment, W is a bond and R^(W) is NH₂. Inanother embodiment, W is a bond and R^(W) is NHR′. In anotherembodiment, W is a bond and R^(W) is CN. In another embodiment, W is abond and R^(W) is CF₃. In another embodiment, W is a bond and R^(W) isOCF₃.

In another embodiment, the invention features a compound of formulaI-C-1 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. In another embodiment, Wis CH₃, CH₂CH₃, CH₂CH₂CH₃, or isopropyl. In another embodiment, W isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen,wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O—, —CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. Inanother embodiment, W is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, or O-isopropyl. Inanother embodiment, W is OCH₂CF₃, OCH₂CH₂CH₂CF₃, or OCHF₂. In anotherembodiment, W is OCH₂CH₂OCH₃, CH₂OH, OC(CH₃)₃, or CH₂CH₂OCH₃.

In another embodiment, the invention features a compound of formulaI-C-1 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂,CN, CF₃, or OCF₃. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or—SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO—, or —SO₂—, and R^(W) is H, OH, NH₂, or NHR′. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H. In another embodiment, W is C₁ alkylwherein one CH₂ unit of said C₁ alkyl is replaced with —CO— and R^(W) isOH. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁alkyl is replaced with —CO— and R^(W) is NH₂. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—and R^(W) is NHR′. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is H, OH, NH₂, orNHR′. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of saidC₁ alkyl is replaced with —SO₂— and R^(W) is H. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —SO₂—and R^(W) is OH. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is NH₂. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —SO₂— and R^(W) is NHR′.

In another embodiment, the invention features a compound of formulaI-C-1 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) absent. In another embodiment, W isC₂ alkyl wherein one CH₂ unit of said C₂ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is absent. In another embodiment, Wis C₂ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—,or —SO₂—, and R^(W) is absent.

In another embodiment, the invention features a compound of formulaI-C-1 and the attendant definitions, wherein W is a bond and R^(W) is a3-6 membered saturated, partially unsaturated, or fully unsaturatedmonocyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In another embodiment, W is a bond andR^(W) is a 5-membered aromatic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In another embodiment, W is abond and R^(W) is a 5-membered aromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In anotherembodiment, W is a bond and R^(W) is pyrrolyl, pyrazolyl, thiazolyl,thiadiazolyl, imidazolyl, oxazolyl, triazolyl, or tetrazolyl.

In another embodiment, the invention features a compound of formulaI-C-1 and the attendant definitions, wherein ring A₁ is selected from:

In another embodiment, the invention features a compound of formulaI-C-1 and the attendant definitions, wherein R¹ is H. In anotherembodiment, R¹ is halogen. In another embodiment, R¹ is CN. In anotherembodiment, R¹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R¹ is CF₃.

In another embodiment, the invention features a compound of formulaI-C-1 and the attendant definitions, wherein R² is H. In anotherembodiment, R² is halogen. In another embodiment, R² is Cl. In anotherembodiment, R² is F. In another embodiment, R² is CN. In anotherembodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R² is CF₃. In anotherembodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replacedwith —O—. In another embodiment, R² is OCF₃. In another embodiment, R²is F, Cl, CN, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formulaI-C-1 and the attendant definitions, wherein R³ is H. In anotherembodiment, R³ is halogen. In another embodiment, R³ is Cl. In anotherembodiment, R³ is F. In another embodiment, R³ is CN. In anotherembodiment, R³ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R³ is t-butyl. In anotherembodiment, R³ is CF₃. In another embodiment, R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formulaI-C-1 and the attendant definitions, wherein R⁴ is H. In anotherembodiment, R⁴ is halogen. In another embodiment, R⁴ is CN. In anotherembodiment, R⁴ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R⁴ is CF₃.

In another embodiment, the invention features a compound of formulaI-C-1 and the attendant definitions, wherein R¹, R², R³, and R⁴ is H.

In another embodiment, the invention features a compound of formulaI-C-1 and the attendant definitions, wherein R⁵ is halogen. In anotherembodiment, R⁵ is Cl. In another embodiment, R⁵ is F. In anotherembodiment, R⁵ is CN. In another embodiment, R⁵ is —X—R^(X). In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁵ is CH₃. In another embodiment, R⁵ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁵ is OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, or OCH(CH₃)₂. In another embodiment, R⁵ is OCH₃. In anotherembodiment, R⁵ is CH₂OH. In another embodiment, R⁵ is OCF₃. In anotherembodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formulaI-C-1 and the attendant definitions, wherein ring A is selected from:

In another aspect, the invention provides a compound of formula I-C-2:

-   or a pharmaceutically acceptable salt thereof,-   wherein, independently for each occurrence:-   Y is C or N;-   m is an integer from 0 to 5 inclusive;-   W is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or —SO₂—;-   R^(W) is absent, H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, OCF₃, or a    3-6 membered saturated, partially unsaturated, or fully unsaturated    monocyclic ring having 0-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   R′ is C₁-C₆ alkyl;-   R¹ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen and wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R² is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R³ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁴ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁷ is halogen, CN, or —X—R^(X);-   X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—; and-   R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to two    non-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced    with —O— and said C₃-C₈ cycloaliphatic is substituted with 0-3    substituents selected from halogen and C₁-C₄ alkyl.

In one embodiment, the invention features a compound of formula I-C-2and the attendant definitions, wherein Y is C. In another embodiment, Yis N.

In another embodiment, the invention features a compound of formulaI-C-2 and the attendant definitions, wherein m is zero. In anotherembodiment, m is an integer from 1 to 5. In another embodiment, m is 1.In another embodiment, m is 2. In another embodiment, m is 3. In anotherembodiment, m is 4. In another embodiment, m is 5.

In another embodiment, the invention features a compound of formulaI-C-2 and the attendant definitions, wherein W is a bond and R^(W) ishalogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. In another embodiment, Wis a bond and R^(W) is halogen. In another embodiment, W is a bond andR^(W) is OH. In another embodiment, W is a bond and R^(W) is NH₂. Inanother embodiment, W is a bond and R^(W) is NHR′. In anotherembodiment, W is a bond and R^(W) is CN. In another embodiment, W is abond and R^(W) is CF₃. In another embodiment, W is a bond and R^(W) isOCF₃.

In another embodiment, the invention features a compound of formulaI-C-2 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. In another embodiment, Wis CH₃, CH₂CH₃, CH₂CH₂CH₃, or isopropyl. In another embodiment, W isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen,wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O—, —CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. Inanother embodiment, W is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, or O-isopropyl. Inanother embodiment, W is OCH₂CF₃, OCH₂CH₂CH₂CF₃, or OCHF₂. In anotherembodiment, W is OCH₂CH₂OCH₃, CH₂OH, OC(CH₃)₃, or CH₂CH₂OCH₃.

In another embodiment, the invention features a compound of formulaI-C-2 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂,CN, CF₃, or OCF₃. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or—SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO—, or —SO₂—, and R^(W) is H, OH, NH₂, or NHR′. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H. In another embodiment, W is C₁ alkylwherein one CH₂ unit of said C₁ alkyl is replaced with —CO— and R^(W) isOH. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁alkyl is replaced with —CO— and R^(W) is NH₂. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—and R^(W) is NHR′. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is H, OH, NH₂, orNHR′. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of saidC₁ alkyl is replaced with —SO₂— and R^(W) is H. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —SO₂—and R^(W) is OH. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is NH₂. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —SO₂— and R^(W) is NHR′.

In another embodiment, the invention features a compound of formulaI-C-2 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) absent. In another embodiment, W isC₂ alkyl wherein one CH₂ unit of said C₂ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is absent. In another embodiment, Wis C₂ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—,or —SO₂—, and R^(W) is absent.

In another embodiment, the invention features a compound of formulaI-C-2 and the attendant definitions, wherein W is a bond and R^(W) is a3-6 membered saturated, partially unsaturated, or fully unsaturatedmonocyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In another embodiment, W is a bond andR^(W) is a 5-membered aromatic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In another embodiment, W is abond and R^(W) is a 5-membered aromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In anotherembodiment, W is a bond and R^(W) is pyrrolyl, pyrazolyl, thiazolyl,thiadiazolyl, imidazolyl, oxazolyl, triazolyl, or tetrazolyl.

In another embodiment, the invention features a compound of formulaI-C-2 and the attendant definitions, wherein ring A₁ is selected from:

In another embodiment, the invention features a compound of formulaI-C-2 and the attendant definitions, wherein R¹ is H. In anotherembodiment, R¹ is halogen. In another embodiment, R¹ is CN. In anotherembodiment, R¹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R¹ is CF₃.

In another embodiment, the invention features a compound of formulaI-C-2 and the attendant definitions, wherein R² is H. In anotherembodiment, R² is halogen. In another embodiment, R² is Cl. In anotherembodiment, R² is F. In another embodiment, R² is CN. In anotherembodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R² is CF₃. In anotherembodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replacedwith —O—. In another embodiment, R² is OCF₃. In another embodiment, R²is F, Cl, CN, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formulaI-C-2 and the attendant definitions, wherein R³ is H. In anotherembodiment, R³ is halogen. In another embodiment, R³ is Cl. In anotherembodiment, R³ is F. In another embodiment, R³ is CN. In anotherembodiment, R³ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R³ is t-butyl. In anotherembodiment, R³ is CF₃. In another embodiment, R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formulaI-C-2 and the attendant definitions, wherein R⁴ is H. In anotherembodiment, R⁴ is halogen. In another embodiment, R⁴ is CN. In anotherembodiment, R⁴ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R⁴ is CF₃.

In another embodiment, the invention features a compound of formulaI-C-2 and the attendant definitions, wherein R¹, R², R³, and R⁴ is H.

In another embodiment, the invention features a compound of formulaI-C-2 and the attendant definitions, wherein R⁷ is halogen. In anotherembodiment, R⁷ is Cl. In another embodiment, R⁷ is F. In anotherembodiment, R⁷ is CN. In another embodiment, R⁷ is —X—R^(X). In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. In anotherembodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formulaI-C-2 wherein R⁷ is —X—R^(X) wherein X is a bond and R^(X) is C₃-C₈cycloaliphatic and said C₃-C₈ cycloaliphatic is substituted with 0-3substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is a bond and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formulaI-C-2 and the attendant definitions, wherein R⁷ is —X—R^(X) wherein X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O— and R^(X)is C₃-C₈ cycloaliphatic and said C₃-C₈ cycloaliphatic is substitutedwith up 0-3 substituents selected from halogen and C₁-C₄ alkyl. Inanother embodiment, R⁷ is —X—R^(X) wherein X is OCH₂ and R^(X) iscyclopropyl.

In another embodiment, the invention features a compound of formulaI-C-2 and the attendant definitions, wherein ring A is selected from:

In another aspect, the invention provides a compound of formula I-C-3:

-   or a pharmaceutically acceptable salt thereof,-   wherein, independently for each occurrence:-   Y is C or N;-   m is an integer from 0 to 5 inclusive;-   W is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or —SO₂—;-   R^(W) is absent, H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, OCF₃, or a    3-6 membered saturated, partially unsaturated, or fully unsaturated    monocyclic ring having 0-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   R′ is C₁-C₆ alkyl;-   R¹ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen and wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R² is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R³ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁴ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁶ is halogen, CN, or —X—R^(X);-   R⁷ is halogen, CN, or —X—R^(X);-   X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—; and-   R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to two    non-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced    with —O— and said C₃-C₈ cycloaliphatic is substituted with 0-3    substituents selected from halogen and C₁-C₄ alkyl.

In one embodiment, the invention features a compound of formula I-C-3and the attendant definitions, wherein Y is C. In another embodiment, Yis N.

In another embodiment, the invention features a compound of formulaI-C-3 and the attendant definitions, wherein m is zero. In anotherembodiment, m is an integer from 1 to 5. In another embodiment, m is 1.In another embodiment, m is 2. In another embodiment, m is 3. In anotherembodiment, m is 4. In another embodiment, m is 5.

In another embodiment, the invention features a compound of formulaI-C-3 and the attendant definitions, wherein W is a bond and R^(W) ishalogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. In another embodiment, Wis a bond and R^(W) is halogen. In another embodiment, W is a bond andR^(W) is OH. In another embodiment, W is a bond and R^(W) is NH₂. Inanother embodiment, W is a bond and R^(W) is NHR′. In anotherembodiment, W is a bond and R^(W) is CN. In another embodiment, W is abond and R^(W) is CF₃. In another embodiment, W is a bond and R^(W) isOCF₃.

In another embodiment, the invention features a compound of formulaI-C-3 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. In another embodiment, Wis CH₃, CH₂CH₃, CH₂CH₂CH₃, or isopropyl. In another embodiment, W isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen,wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O—, —CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. Inanother embodiment, W is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, or O-isopropyl. Inanother embodiment, W is OCH₂CF₃, OCH₂CH₂CH₂CF₃, or OCHF₂. In anotherembodiment, W is OCH₂CH₂OCH₃, CH₂OH, OC(CH₃)₃, or CH₂CH₂OCH₃.

In another embodiment, the invention features a compound of formulaI-C-3 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂,CN, CF₃, or OCF₃. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or—SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO—, or —SO₂—, and R^(W) is H, OH, NH₂, or NHR′. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H. In another embodiment, W is C₁ alkylwherein one CH₂ unit of said C₁ alkyl is replaced with —CO— and R^(W) isOH. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁alkyl is replaced with —CO— and R^(W) is NH₂. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—and R^(W) is NHR′. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is H, OH, NH₂, orNHR′. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of saidC₁ alkyl is replaced with —SO₂— and R^(W) is H. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —SO₂—and R^(W) is OH. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is NH₂. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —SO₂— and R^(W) is NHR′.

In another embodiment, the invention features a compound of formulaI-C-3 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) absent. In another embodiment, W isC₂ alkyl wherein one CH₂ unit of said C₂ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is absent. In another embodiment, Wis C₂ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—,or —SO₂—, and R^(W) is absent.

In another embodiment, the invention features a compound of formulaI-C-3 and the attendant definitions, wherein W is a bond and R^(W) is a3-6 membered saturated, partially unsaturated, or fully unsaturatedmonocyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In another embodiment, W is a bond andR^(W) is a 5-membered aromatic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In another embodiment, W is abond and R^(W) is a 5-membered aromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In anotherembodiment, W is a bond and R^(W) is pyrrolyl, pyrazolyl, thiazolyl,thiadiazolyl, imidazolyl, oxazolyl, triazolyl, or tetrazolyl.

In another embodiment, the invention features a compound of formulaI-C-3 and the attendant definitions, wherein ring A₁ is selected from:

In another embodiment, the invention features a compound of formulaI-C-3 and the attendant definitions, wherein R¹ is H. In anotherembodiment, R¹ is halogen. In another embodiment, R¹ is CN. In anotherembodiment, R¹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R¹ is CF₃.

In another embodiment, the invention features a compound of formulaI-C-3 and the attendant definitions, wherein R² is H. In anotherembodiment, R² is halogen. In another embodiment, R² is Cl. In anotherembodiment, R² is F. In another embodiment, R² is CN. In anotherembodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R² is CF₃. In anotherembodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replacedwith —O—. In another embodiment, R² is OCF₃. In another embodiment, R²is F, Cl, CN, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formulaI-C-3 and the attendant definitions, wherein R³ is H. In anotherembodiment, R³ is halogen. In another embodiment, R³ is Cl. In anotherembodiment, R³ is F. In another embodiment, R³ is CN. In anotherembodiment, R³ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R³ is t-butyl. In anotherembodiment, R³ is CF₃. In another embodiment, R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formulaI-C-3 and the attendant definitions, wherein R⁴ is H. In anotherembodiment, R⁴ is halogen. In another embodiment, R⁴ is CN. In anotherembodiment, R⁴ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R⁴ is CF₃.

In another embodiment, the invention features a compound of formulaI-C-3 and the attendant definitions, wherein R¹, R², R³, and R⁴ is H.

In another embodiment, the invention features a compound of formulaI-C-3 and the attendant definitions, R⁶ is halogen. In anotherembodiment, R⁶ is Cl. In another embodiment, R⁶ is F. In anotherembodiment, R⁶ is CN. In another embodiment, R⁶ is —X—R^(X). In anotherembodiment, R⁶ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁶ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁶ is CH₃. In another embodiment, R⁶ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁶ is OCH₃.

In another embodiment, the invention features a compound of formulaI-C-3 and the attendant definitions, wherein R⁷ is halogen. In anotherembodiment, R⁷ is Cl. In another embodiment, R⁷ is F. In anotherembodiment, R⁷ is CN. In another embodiment, R⁷ is —X—R^(X). In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. In anotherembodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formulaI-C-3 wherein R⁷ is —X—R^(X) wherein X is a bond and R^(X) is C₃-C₈cycloaliphatic and said C₃-C₈ cycloaliphatic is substituted with 0-3substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is a bond and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formulaI-C-3 and the attendant definitions, wherein R⁷ is —X—R^(X) wherein X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O— and R^(X)is C₃-C₈ cycloaliphatic and said C₃-C₈ cycloaliphatic is substitutedwith up 0-3 substituents selected from halogen and C₁-C₄ alkyl. Inanother embodiment, R⁷ is —X—R^(X) wherein X is OCH₂ and R^(X) iscyclopropyl.

In another embodiment, the invention features a compound of formulaI-C-3 and the attendant definitions, wherein ring A is selected from:

In another aspect, the invention provides a compound of formula I-C-4:

-   or a pharmaceutically acceptable salt thereof, wherein,    independently for each occurrence:-   Y is C or N;-   m is an integer from 0 to 5 inclusive;-   W is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or —SO₂—;-   R^(W) is absent, H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, OCF₃, or a    3-6 membered saturated, partially unsaturated, or fully unsaturated    monocyclic ring having 0-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   R′ is C₁-C₆ alkyl;-   R¹ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen and wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R² is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R³ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁴ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁵ is halogen, CN, or —X—R^(X);-   R⁷ is halogen, CN, or —X—R^(X);-   X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—; and-   R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to two    non-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced    with —O— and said C₃-C₈ cycloaliphatic is substituted with 0-3    substituents selected from halogen and C₁-C₄ alkyl.

In one embodiment, the invention features a compound of formula I-C-4and the attendant definitions, wherein Y is C. In another embodiment, Yis N.

In another embodiment, the invention features a compound of formulaI-C-4 and the attendant definitions, wherein m is zero. In anotherembodiment, m is an integer from 1 to 5. In another embodiment, m is 1.In another embodiment, m is 2. In another embodiment, m is 3. In anotherembodiment, m is 4. In another embodiment, m is 5.

In another embodiment, the invention features a compound of formulaI-C-4 and the attendant definitions, wherein W is a bond and R^(W) ishalogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. In another embodiment, Wis a bond and R^(W) is halogen. In another embodiment, W is a bond andR^(W) is OH. In another embodiment, W is a bond and R^(W) is NH₂. Inanother embodiment, W is a bond and R^(W) is NHR′. In anotherembodiment, W is a bond and R^(W) is CN. In another embodiment, W is abond and R^(W) is CF₃. In another embodiment, W is a bond and R^(W) isOCF₃.

In another embodiment, the invention features a compound of formulaI-C-4 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. In another embodiment, Wis CH₃, CH₂CH₃, CH₂CH₂CH₃, or isopropyl. In another embodiment, W isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen,wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O—, —CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. Inanother embodiment, W is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, or O-isopropyl. Inanother embodiment, W is OCH₂CF₃, OCH₂CH₂CH₂CF₃, or OCHF₂. In anotherembodiment, W is OCH₂CH₂OCH₃, CH₂OH, OC(CH₃)₃, or CH₂CH₂OCH₃.

In another embodiment, the invention features a compound of formulaI-C-4 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂,CN, CF₃, or OCF₃. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or—SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO—, or —SO₂—, and R^(W) is H, OH, NH₂, or NHR′. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H. In another embodiment, W is C₁ alkylwherein one CH₂ unit of said C₁ alkyl is replaced with —CO— and R^(W) isOH. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁alkyl is replaced with —CO— and R^(W) is NH₂. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—and R^(W) is NHR′. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is H, OH, NH₂, orNHR′. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of saidC₁ alkyl is replaced with —SO₂— and R^(W) is H. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —SO₂—and R^(W) is OH. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is NH₂. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —SO₂— and R^(W) is NHR′.

In another embodiment, the invention features a compound of formulaI-C-4 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) absent. In another embodiment, W isC₂ alkyl wherein one CH₂ unit of said C₂ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is absent. In another embodiment, Wis C₂ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—,or —SO₂—, and R^(W) is absent.

In another embodiment, the invention features a compound of formulaI-C-4 and the attendant definitions, wherein W is a bond and R^(W) is a3-6 membered saturated, partially unsaturated, or fully unsaturatedmonocyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In another embodiment, W is a bond andR^(W) is a 5-membered aromatic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In another embodiment, W is abond and R^(W) is a 5-membered aromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In anotherembodiment, W is a bond and R^(W) is pyrrolyl, pyrazolyl, thiazolyl,thiadiazolyl, imidazolyl, oxazolyl, triazolyl, or tetrazolyl.

In another embodiment, the invention features a compound of formulaI-C-4 and the attendant definitions, wherein ring A₁ is selected from:

In another embodiment, the invention features a compound of formulaI-C-4 and the attendant definitions, wherein R¹ is H. In anotherembodiment, R¹ is halogen. In another embodiment, R¹ is CN. In anotherembodiment, R¹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R¹ is CF₃.

In another embodiment, the invention features a compound of formulaI-C-4 and the attendant definitions, wherein R² is H. In anotherembodiment, R² is halogen. In another embodiment, R² is Cl. In anotherembodiment, R² is F. In another embodiment, R² is CN. In anotherembodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R² is CF₃. In anotherembodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replacedwith —O—. In another embodiment, R² is OCF₃. In another embodiment, R²is F, Cl, CN, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formulaI-C-4 and the attendant definitions, wherein R³ is H. In anotherembodiment, R³ is halogen. In another embodiment, R³ is Cl. In anotherembodiment, R³ is F. In another embodiment, R³ is CN. In anotherembodiment, R³ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R³ is t-butyl. In anotherembodiment, R³ is CF₃. In another embodiment, R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formulaI-C-4 and the attendant definitions, wherein R⁴ is H. In anotherembodiment, R⁴ is halogen. In another embodiment, R⁴ is CN. In anotherembodiment, R⁴ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R⁴ is CF₃.

In another embodiment, the invention features a compound of formulaI-C-4 and the attendant definitions, wherein R¹, R², R³, and R⁴ is H.

In another embodiment, the invention features a compound of formulaI-C-4 and the attendant definitions, wherein R⁵ is halogen. In anotherembodiment, R⁵ is Cl. In another embodiment, R⁵ is F. In anotherembodiment, R⁵ is CN. In another embodiment, R⁵ is —X—R^(X). In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁵ is CH₃. In another embodiment, R⁵ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁵ is OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, or OCH(CH₃)₂. In another embodiment, R⁵ is OCH₃. In anotherembodiment, R⁵ is CH₂OH. In another embodiment, R⁵ is OCF₃. In anotherembodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formulaI-C-4 and the attendant definitions, wherein R⁷ is H. In anotherembodiment, R⁷ is halogen. In another embodiment, R⁷ is Cl. In anotherembodiment, R⁷ is F. In another embodiment, R⁷ is CN. In anotherembodiment, R⁷ is —X—R^(X). In another embodiment, R⁷ is —X—R^(X)wherein R^(X) is absent. In another embodiment, R⁷ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen. In another embodiment, R⁷ is CH₃, CH₂CH₃,CH₂CH₂CH₃ or isopropyl. In another embodiment, R⁷ is CF₃. In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen wherein twonon-adjacent CH₂ units of said C₁-C₆ alkyl are replaced with —O—. Inanother embodiment, R⁷ is OCH₂CH₂OCH₃. In another embodiment, R⁷ is—X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆alkyl is substituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆alkyl is replaced with —O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, OC(CH₃)₃, CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃,OCH₂CF₃, OCH₂CH₂CH₂CF₃, or OCHF₂.

In another embodiment, the invention features a compound of formulaI-C-4 wherein R⁷ is —X—R^(X) wherein X is a bond and R^(X) is C₃-C₈cycloaliphatic and said C₃-C₈ cycloaliphatic is substituted with 0-3substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is a bond and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formulaI-C-4 and the attendant definitions, wherein R⁷ is —X—R^(X) wherein X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O— and R^(X)is C₃-C₈ cycloaliphatic and said C₃-C₈ cycloaliphatic is substitutedwith up 0-3 substituents selected from halogen and C₁-C₄ alkyl. Inanother embodiment, R⁷ is —X—R^(X) wherein X is OCH₂ and R^(X) iscyclopropyl.

In another embodiment, the invention features a compound of formulaI-C-4 and the attendant definitions, wherein ring A is selected from:

In another aspect, the invention provides a compound of formula I-D:

-   or a pharmaceutically acceptable salt thereof,-   wherein, independently for each occurrence:-   Y is C or N;-   m is an integer from 0 to 5 inclusive;-   W is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or —SO₂—;-   R^(W) is absent, H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, OCF₃, or a    3-6 membered saturated, partially unsaturated, or fully unsaturated    monocyclic ring having 0-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   R′ is C₁-C₆ alkyl;-   R¹ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen and wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R² is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R³ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁴ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁵ is H, halogen, CN, or —X—R^(X); R^(5′) is H, halogen, CN, or    —X—R^(X); R⁶ is H, halogen, CN, or —X—R^(X); R^(6′) is H, halogen,    CN, or —X—R^(X); R⁷ is H, halogen, CN, or —X—R^(X);-   X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—; and-   R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to two    non-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced    with —O— and said C₃-C₈ cycloaliphatic is substituted with 0-3    substituents selected from halogen and C₁-C₄ alkyl.

In one embodiment, the invention features a compound of formula I-D andthe attendant definitions, wherein Y is C. In another embodiment, Y isN.

In another embodiment, the invention features a compound of formula I-Dand the attendant definitions, wherein m is zero. In another embodiment,m is an integer from 1 to 5. In another embodiment, m is 1. In anotherembodiment, m is 2. In another embodiment, m is 3. In anotherembodiment, m is 4. In another embodiment, m is 5.

In another embodiment, the invention features a compound of formula I-Dand the attendant definitions, wherein W is a bond and R^(W) is halogen,OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. In another embodiment, W is a bondand R^(W) is halogen. In another embodiment, W is a bond and R^(W) isOH. In another embodiment, W is a bond and R^(W) is NH₂. In anotherembodiment, W is a bond and R^(W) is NHR′. In another embodiment, W is abond and R^(W) is CN. In another embodiment, W is a bond and R^(W) isCF₃. In another embodiment, W is a bond and R^(W) is OCF₃.

In another embodiment, the invention features a compound of formula I-Dand the attendant definitions, wherein W is C₁-C₆ alkyl wherein saidC₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. In another embodiment, Wis CH₃, CH₂CH₃, CH₂CH₂CH₃, or isopropyl. In another embodiment, W isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen,wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O—, —CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. Inanother embodiment, W is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, or O-isopropyl. Inanother embodiment, W is OCH₂CF₃, OCH₂CH₂CH₂CF₃, or OCHF₂. In anotherembodiment, W is OCH₂CH₂OCH₃, CH₂OH, OC(CH₃)₃, or CH₂CH₂OCH₃.

In another embodiment, the invention features a compound of formula I-Dand the attendant definitions, wherein W is C₁-C₆ alkyl wherein saidC₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂,CN, CF₃, or OCF₃. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or—SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO—, or —SO₂—, and R^(W) is H, OH, NH₂, or NHR′. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H. In another embodiment, W is C₁ alkylwherein one CH₂ unit of said C₁ alkyl is replaced with —CO— and R^(W) isOH. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁alkyl is replaced with —CO— and R^(W) is NH₂. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—and R^(W) is NHR′. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is H, OH, NH₂, orNHR′. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of saidC₁ alkyl is replaced with —SO₂— and R^(W) is H. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —SO₂—and R^(W) is OH. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is NH₂. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —SO₂— and R^(W) is NHR′.

In another embodiment, the invention features a compound of formula I-Dand the attendant definitions, wherein W is C₁-C₆ alkyl wherein saidC₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) absent. In another embodiment, W isC₂ alkyl wherein one CH₂ unit of said C₂ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is absent. In another embodiment, Wis C₂ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—,or —SO₂—, and R^(W) is absent.

In another embodiment, the invention features a compound of formula I-Dand the attendant definitions, wherein W is a bond and R^(W) is a 3-6membered saturated, partially unsaturated, or fully unsaturatedmonocyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In another embodiment, W is a bond andR^(W) is a 5-membered aromatic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In another embodiment, W is abond and R^(W) is a 5-membered aromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In anotherembodiment, W is a bond and R^(W) is pyrrolyl, pyrazolyl, thiazolyl,thiadiazolyl, imidazolyl, oxazolyl, triazolyl, or tetrazolyl.

In another embodiment, the invention features a compound of formula I-Dand the attendant definitions, wherein ring A₁ is selected from:

In another embodiment, the invention features a compound of formula I-Dand the attendant definitions, wherein R¹ is H. In another embodiment,R¹ is halogen. In another embodiment, R¹ is CN. In another embodiment,R¹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen. In another embodiment, R¹ is CF₃.

In another embodiment, the invention features a compound of formula I-Dand the attendant definitions, wherein R² is H. In another embodiment,R² is halogen. In another embodiment, R² is Cl. In another embodiment,R² is F. In another embodiment, R² is CN. In another embodiment, R² isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R² is CF₃. In another embodiment, R² is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen wherein one CH₂unit of said C₁-C₆ alkyl is replaced with —O—. In another embodiment, R²is OCF₃. In another embodiment, R² is F, Cl, CN, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formula I-Dand the attendant definitions, wherein R³ is H. In another embodiment,R³ is halogen. In another embodiment, R³ is Cl. In another embodiment,R³ is F. In another embodiment, R³ is CN. In another embodiment, R³ isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R³ is t-butyl. In another embodiment, R³ is CF₃. Inanother embodiment, R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formula I-Dand the attendant definitions, wherein R⁴ is H. In another embodiment,R⁴ is halogen. In another embodiment, R⁴ is CN. In another embodiment,R⁴ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen. In another embodiment, R⁴ is CF₃.

In another embodiment, the invention features a compound of formula I-Dand the attendant definitions, wherein R¹, R², R³, and R⁴ is H.

In another embodiment, the invention features a compound of formula I-Dand the attendant definitions, wherein R⁵ is H. In another embodiment,R⁵ is halogen. In another embodiment, R⁵ is Cl. In another embodiment,R⁵ is F. In another embodiment, R⁵ is CN. In another embodiment, R⁵ is—X—R^(X). In another embodiment, R⁵ is —X—R^(X) wherein R^(X) is absent.In another embodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R⁵ is CH₃. In another embodiment, R⁵ is —X—R^(X)wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁵ is OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, or OCH(CH₃)₂. In another embodiment, R⁵ is OCH₃. In anotherembodiment, R⁵ is CH₂OH. In another embodiment, R⁵ is OCF₃. In anotherembodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula I-Dand the attendant definitions, wherein R^(5′) is H. In anotherembodiment, R^(5′) is halogen. In another embodiment, R^(5′) is Cl. Inanother embodiment, R^(5′) is F. In another embodiment, R^(5′) is CN. Inanother embodiment, R^(5′) is —X—R^(X). In another embodiment, R^(5′) is—X—R^(X) wherein R^(X) is absent. In another embodiment, R^(5′) is—X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆alkyl is substituted with 0-6 halogen. In another embodiment, R^(5′) isCH₃. In another embodiment, R^(5′) is —X—R^(X) wherein R^(X) is absentand X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O—.In another embodiment, R^(5′) is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, orOCH(CH₃)₂. In another embodiment, R^(5′) is OCH₃. In another embodiment,R^(5′) is CH₂OH. In another embodiment, R^(5′) is OCF₃. In anotherembodiment, R^(5′) is OCHF₂.

In another embodiment, the invention features a compound of formula I-Dand the attendant definitions, R⁶ is H. In another embodiment, R⁶ ishalogen. In another embodiment, R⁶ is Cl. In another embodiment, R⁶ isF. In another embodiment, R⁶ is CN. In another embodiment, R⁶ is—X—R^(X). In another embodiment, R⁶ is —X—R^(X) wherein R^(X) is absent.In another embodiment, R⁶ is —X—R^(X) wherein R^(X) is absent and X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R⁶ is CH₃. In another embodiment, R⁶ is —X—R^(X)wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁶ is OCH₃.

In another embodiment, the invention features a compound of formula I-Dand the attendant definitions, wherein R^(6′) is H. In anotherembodiment, R^(6′) is halogen. In another embodiment, R^(6′) is Cl. Inanother embodiment, R^(6′) is F. In another embodiment, R^(6′) is CN. Inanother embodiment, R^(6′) is —X—R^(X). In another embodiment, R^(6′) is—X—R^(X) wherein R^(X) is absent. In another embodiment, R^(6′) is—X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆alkyl is substituted with 0-6 halogen. In another embodiment, R^(6′) isCH₃. In another embodiment, R^(6′) is —X—R^(X) wherein R^(X) is absentand X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O—.In another embodiment, R^(6′) is OCH₃.

In another embodiment, the invention features a compound of formula I-Dand the attendant definitions, wherein R⁷ is H. In another embodiment,R⁷ is halogen. In another embodiment, R⁷ is Cl. In another embodiment,R⁷ is F. In another embodiment, R⁷ is CN. In another embodiment, R⁷ is—X—R^(X). In another embodiment, R⁷ is —X—R^(X) wherein R^(X) is absent.In another embodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. Inanother embodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X)wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formula I-Dwherein R⁷ is —X—R^(X) wherein X is a bond and R^(X) is C₃-C₈cycloaliphatic and said C₃-C₈ cycloaliphatic is substituted with 0-3substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is a bond and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Dand the attendant definitions, wherein R⁷ is —X—R^(X) wherein X is C₁-C₆alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen whereinone CH₂ unit of said C₁-C₆ alkyl is replaced with —O— and R^(X) is C₃-C₈cycloaliphatic and said C₃-C₈ cycloaliphatic is substituted with up 0-3substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is OCH₂ and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Dand the attendant definitions, wherein ring A is selected from:

In another aspect, the invention provides a compound of formula I-D-1:

-   or a pharmaceutically acceptable salt thereof,-   wherein, independently for each occurrence:-   Y is C or N;-   m is an integer from 0 to 5 inclusive;-   W is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or —SO₂—;-   R^(W) is absent, H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, OCF₃, or a    3-6 membered saturated, partially unsaturated, or fully unsaturated    monocyclic ring having 0-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   R′ is C₁-C₆ alkyl;-   R¹ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen and wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R² is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R³ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁴ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁵ is halogen, CN, or —X—R^(X);-   X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—; and-   R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to two    non-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced    with —O— and said C₃-C₈ cycloaliphatic is substituted with 0-3    substituents selected from halogen and C₁-C₄ alkyl.

In one embodiment, the invention features a compound of formula I-D-1and the attendant definitions, wherein Y is C. In another embodiment, Yis N.

In another embodiment, the invention features a compound of formulaI-D-1 and the attendant definitions, wherein m is zero. In anotherembodiment, m is an integer from 1 to 5. In another embodiment, m is 1.In another embodiment, m is 2. In another embodiment, m is 3. In anotherembodiment, m is 4. In another embodiment, m is 5.

In another embodiment, the invention features a compound of formulaI-D-1 and the attendant definitions, wherein W is a bond and R^(W) ishalogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. In another embodiment, Wis a bond and R^(W) is halogen. In another embodiment, W is a bond andR^(W) is OH. In another embodiment, W is a bond and R^(W) is NH₂. Inanother embodiment, W is a bond and R^(W) is NHR′. In anotherembodiment, W is a bond and R^(W) is CN. In another embodiment, W is abond and R^(W) is CF₃. In another embodiment, W is a bond and R^(W) isOCF₃.

In another embodiment, the invention features a compound of formulaI-D-1 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. In another embodiment, Wis CH₃, CH₂CH₃, CH₂CH₂CH₃, or isopropyl. In another embodiment, W isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen,wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O—, —CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. Inanother embodiment, W is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, or O-isopropyl. Inanother embodiment, W is OCH₂CF₃, OCH₂CH₂CH₂CF₃, or OCHF₂. In anotherembodiment, W is OCH₂CH₂OCH₃, CH₂OH, OC(CH₃)₃, or CH₂CH₂OCH₃.

In another embodiment, the invention features a compound of formulaI-D-1 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂,CN, CF₃, or OCF₃. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or—SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO—, or —SO₂—, and R^(W) is H, OH, NH₂, or NHR′. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H. In another embodiment, W is C₁ alkylwherein one CH₂ unit of said C₁ alkyl is replaced with —CO— and R^(W) isOH. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁alkyl is replaced with —CO— and R^(W) is NH₂. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—and R^(W) is NHR′. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is H, OH, NH₂, orNHR′. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of saidC₁ alkyl is replaced with —SO₂— and R^(W) is H. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —SO₂—and R^(W) is OH. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is NH₂. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —SO₂— and R^(W) is NHR′.

In another embodiment, the invention features a compound of formulaI-D-1 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) absent. In another embodiment, W isC₂ alkyl wherein one CH₂ unit of said C₂ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is absent. In another embodiment, Wis C₂ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—,or —SO₂—, and R^(W) is absent.

In another embodiment, the invention features a compound of formulaI-D-1 and the attendant definitions, wherein W is a bond and R^(W) is a3-6 membered saturated, partially unsaturated, or fully unsaturatedmonocyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In another embodiment, W is a bond andR^(W) is a 5-membered aromatic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In another embodiment, W is abond and R^(W) is a 5-membered aromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In anotherembodiment, W is a bond and R^(W) is pyrrolyl, pyrazolyl, thiazolyl,thiadiazolyl, imidazolyl, oxazolyl, triazolyl, or tetrazolyl.

In another embodiment, the invention features a compound of formulaI-D-1 and the attendant definitions, wherein ring A₁ is selected from:

In another embodiment, the invention features a compound of formulaI-D-1 and the attendant definitions, wherein R¹ is H. In anotherembodiment, R¹ is halogen. In another embodiment, R¹ is CN. In anotherembodiment, R¹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R¹ is CF₃.

In another embodiment, the invention features a compound of formulaI-D-1 and the attendant definitions, wherein R² is H. In anotherembodiment, R² is halogen. In another embodiment, R² is Cl. In anotherembodiment, R² is F. In another embodiment, R² is CN. In anotherembodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R² is CF₃. In anotherembodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replacedwith —O—. In another embodiment, R² is OCF₃. In another embodiment, R²is F, Cl, CN, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formulaI-D-1 and the attendant definitions, wherein R³ is H. In anotherembodiment, R³ is halogen. In another embodiment, R³ is Cl. In anotherembodiment, R³ is F. In another embodiment, R³ is CN. In anotherembodiment, R³ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R³ is t-butyl. In anotherembodiment, R³ is CF₃. In another embodiment, R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formulaI-D-1 and the attendant definitions, wherein R⁴ is H. In anotherembodiment, R⁴ is halogen. In another embodiment, R⁴ is CN. In anotherembodiment, R⁴ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R⁴ is CF₃.

In another embodiment, the invention features a compound of formulaI-D-1 and the attendant definitions, wherein R¹, R², R³, and R⁴ is H.

In another embodiment, the invention features a compound of formulaI-D-1 and the attendant definitions, wherein R⁵ is halogen. In anotherembodiment, R⁵ is Cl. In another embodiment, R⁵ is F. In anotherembodiment, R⁵ is CN. In another embodiment, R⁵ is —X—R^(X). In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁵ is CH₃. In another embodiment, R⁵ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁵ is OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, or OCH(CH₃)₂. In another embodiment, R⁵ is OCH₃. In anotherembodiment, R⁵ is CH₂OH. In another embodiment, R⁵ is OCF₃. In anotherembodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formulaI-D-1 and the attendant definitions, wherein ring A is selected from:

In another aspect, the invention provides a compound of formula I-D-2:

-   or a pharmaceutically acceptable salt thereof,-   wherein, independently for each occurrence:-   Y is C or N;-   m is an integer from 0 to 5 inclusive;-   W is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or —SO₂—;-   R^(W) is absent, H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, OCF₃, or a    3-6 membered saturated, partially unsaturated, or fully unsaturated    monocyclic ring having 0-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   R′ is C₁-C₆ alkyl;-   R¹ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen and wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R² is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R³ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁴ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁷ is halogen, CN, or —X—R^(X);-   X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—; and-   R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to two    non-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced    with —O— and said C₃-C₈ cycloaliphatic is substituted with 0-3    substituents selected from halogen and C₁-C₄ alkyl.

In one embodiment, the invention features a compound of formula I-D-2and the attendant definitions, wherein Y is C. In another embodiment, Yis N.

In another embodiment, the invention features a compound of formulaI-D-2 and the attendant definitions, wherein m is zero. In anotherembodiment, m is an integer from 1 to 5. In another embodiment, m is 1.In another embodiment, m is 2. In another embodiment, m is 3. In anotherembodiment, m is 4. In another embodiment, m is 5.

In another embodiment, the invention features a compound of formulaI-D-2 and the attendant definitions, wherein W is a bond and R^(W) ishalogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. In another embodiment, Wis a bond and R^(W) is halogen. In another embodiment, W is a bond andR^(W) is OH. In another embodiment, W is a bond and R^(W) is NH₂. Inanother embodiment, W is a bond and R^(W) is NHR′. In anotherembodiment, W is a bond and R^(W) is CN. In another embodiment, W is abond and R^(W) is CF₃. In another embodiment, W is a bond and R^(W) isOCF₃.

In another embodiment, the invention features a compound of formulaI-D-2 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. In another embodiment, Wis CH₃, CH₂CH₃, CH₂CH₂CH₃, or isopropyl. In another embodiment, W isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen,wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O—, —CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. Inanother embodiment, W is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, or O-isopropyl. Inanother embodiment, W is OCH₂CF₃, OCH₂CH₂CH₂CF₃, or OCHF₂. In anotherembodiment, W is OCH₂CH₂OCH₃, CH₂OH, OC(CH₃)₃, or CH₂CH₂OCH₃.

In another embodiment, the invention features a compound of formulaI-D-2 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂,CN, CF₃, or OCF₃. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or—SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO—, or —SO₂—, and R^(W) is H, OH, NH₂, or NHR′. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H. In another embodiment, W is C₁ alkylwherein one CH₂ unit of said C₁ alkyl is replaced with —CO— and R^(W) isOH. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁alkyl is replaced with —CO— and R^(W) is NH₂. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—and R^(W) is NHR′. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is H, OH, NH₂, orNHR′. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of saidC₁ alkyl is replaced with —SO₂— and R^(W) is H. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —SO₂—and R^(W) is OH. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is NH₂. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —SO₂— and R^(W) is NHR′.

In another embodiment, the invention features a compound of formulaI-D-2 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) absent. In another embodiment, W isC₂ alkyl wherein one CH₂ unit of said C₂ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is absent. In another embodiment, Wis C₂ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—,or —SO₂—, and R^(W) is absent.

In another embodiment, the invention features a compound of formulaI-D-2 and the attendant definitions, wherein W is a bond and R^(W) is a3-6 membered saturated, partially unsaturated, or fully unsaturatedmonocyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In another embodiment, W is a bond andR^(W) is a 5-membered aromatic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In another embodiment, W is abond and R^(W) is a 5-membered aromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In anotherembodiment, W is a bond and R^(W) is pyrrolyl, pyrazolyl, thiazolyl,thiadiazolyl, imidazolyl, oxazolyl, triazolyl, or tetrazolyl.

In another embodiment, the invention features a compound of formulaI-D-2 and the attendant definitions, wherein ring A₁ is selected from:

In another embodiment, the invention features a compound of formulaI-D-2 and the attendant definitions, wherein R¹ is H. In anotherembodiment, R¹ is halogen. In another embodiment, R¹ is CN. In anotherembodiment, R¹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R¹ is CF₃.

In another embodiment, the invention features a compound of formulaI-D-2 and the attendant definitions, wherein R² is H. In anotherembodiment, R² is halogen. In another embodiment, R² is Cl. In anotherembodiment, R² is F. In another embodiment, R² is CN. In anotherembodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R² is CF₃. In anotherembodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replacedwith —O—. In another embodiment, R² is OCF₃. In another embodiment, R²is F, Cl, CN, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formulaI-D-2 and the attendant definitions, wherein R³ is H. In anotherembodiment, R³ is halogen. In another embodiment, R³ is Cl. In anotherembodiment, R³ is F. In another embodiment, R³ is CN. In anotherembodiment, R³ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R³ is t-butyl. In anotherembodiment, R³ is CF₃. In another embodiment, R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formulaI-D-2 and the attendant definitions, wherein R⁴ is H. In anotherembodiment, R⁴ is halogen. In another embodiment, R⁴ is CN. In anotherembodiment, R⁴ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R⁴ is CF₃.

In another embodiment, the invention features a compound of formulaI-D-2 and the attendant definitions, wherein R¹, R², R³, and R⁴ is H.

In another embodiment, the invention features a compound of formulaI-D-2 and the attendant definitions, wherein R⁷ is halogen. In anotherembodiment, R⁷ is Cl. In another embodiment, R⁷ is F. In anotherembodiment, R⁷ is CN. In another embodiment, R⁷ is —X—R^(X). In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. In anotherembodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formulaI-D-2 wherein R⁷ is —X—R^(X) wherein X is a bond and R^(X) is C₃-C₈cycloaliphatic and said C₃-C₈ cycloaliphatic is substituted with 0-3substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is a bond and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formulaI-D-2 and the attendant definitions, wherein R⁷ is —X—R^(X) wherein X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O— and R^(X)is C₃-C₈ cycloaliphatic and said C₃-C₈ cycloaliphatic is substitutedwith up 0-3 substituents selected from halogen and C₁-C₄ alkyl. Inanother embodiment, R⁷ is —X—R^(X) wherein X is OCH₂ and R^(X) iscyclopropyl.

In another embodiment, the invention features a compound of formulaI-D-2 and the attendant definitions, wherein ring A is selected from:

In another aspect, the invention provides a compound of formula I-D-3:

-   or a pharmaceutically acceptable salt thereof,-   wherein, independently for each occurrence:-   Y is C or N;-   m is an integer from 0 to 5 inclusive;-   W is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or —SO₂—;-   R^(W) is absent, H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, OCF₃, or a    3-6 membered saturated, partially unsaturated, or fully unsaturated    monocyclic ring having 0-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   R′ is C₁-C₆ alkyl;-   R¹ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen and wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R² is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R³ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁴ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁶ is halogen, CN, or —X—R^(X);-   R⁷ is halogen, CN, or —X—R^(X);-   X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—; and-   R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to two    non-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced    with —O— and said C₃-C₈ cycloaliphatic is substituted with 0-3    substituents selected from halogen and C₁-C₄ alkyl.

In one embodiment, the invention features a compound of formula I-D-3and the attendant definitions, wherein Y is C. In another embodiment, Yis N.

In another embodiment, the invention features a compound of formulaI-D-3 and the attendant definitions, wherein m is zero. In anotherembodiment, m is an integer from 1 to 5. In another embodiment, m is 1.In another embodiment, m is 2. In another embodiment, m is 3. In anotherembodiment, m is 4. In another embodiment, m is 5.

In another embodiment, the invention features a compound of formulaI-D-3 and the attendant definitions, wherein W is a bond and R^(W) ishalogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. In another embodiment, Wis a bond and R^(W) is halogen. In another embodiment, W is a bond andR^(W) is OH. In another embodiment, W is a bond and R^(W) is NH₂. Inanother embodiment, W is a bond and R^(W) is NHR′. In anotherembodiment, W is a bond and R^(W) is CN. In another embodiment, W is abond and R^(W) is CF₃. In another embodiment, W is a bond and R^(W) isOCF₃.

In another embodiment, the invention features a compound of formulaI-D-3 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. In another embodiment, Wis CH₃, CH₂CH₃, CH₂CH₂CH₃, or isopropyl. In another embodiment, W isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen,wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O—, —CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. Inanother embodiment, W is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, or O-isopropyl. Inanother embodiment, W is OCH₂CF₃, OCH₂CH₂CH₂CF₃, or OCHF₂. In anotherembodiment, W is OCH₂CH₂OCH₃, CH₂OH, OC(CH₃)₃, or CH₂CH₂OCH₃.

In another embodiment, the invention features a compound of formulaI-D-3 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂,CN, CF₃, or OCF₃. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or—SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO—, or —SO₂—, and R^(W) is H, OH, NH₂, or NHR′. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H. In another embodiment, W is C₁ alkylwherein one CH₂ unit of said C₁ alkyl is replaced with —CO— and R^(W) isOH. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁alkyl is replaced with —CO— and R^(W) is NH₂. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—and R^(W) is NHR′. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is H, OH, NH₂, orNHR′. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of saidC₁ alkyl is replaced with —SO₂— and R^(W) is H. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —SO₂—and R^(W) is OH. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is NH₂. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —SO₂— and R^(W) is NHR′.

In another embodiment, the invention features a compound of formulaI-D-3 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) absent. In another embodiment, W isC₂ alkyl wherein one CH₂ unit of said C₂ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is absent. In another embodiment, Wis C₂ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—,or —SO₂—, and R^(W) is absent.

In another embodiment, the invention features a compound of formulaI-D-3 and the attendant definitions, wherein W is a bond and R^(W) is a3-6 membered saturated, partially unsaturated, or fully unsaturatedmonocyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In another embodiment, W is a bond andR^(W) is a 5-membered aromatic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In another embodiment, W is abond and R^(W) is a 5-membered aromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In anotherembodiment, W is a bond and R^(W) is pyrrolyl, pyrazolyl, thiazolyl,thiadiazolyl, imidazolyl, oxazolyl, triazolyl, or tetrazolyl.

In another embodiment, the invention features a compound of formulaI-D-3 and the attendant definitions, wherein ring A₁ is selected from:

In another embodiment, the invention features a compound of formulaI-D-3 and the attendant definitions, wherein R¹ is H. In anotherembodiment, R¹ is halogen. In another embodiment, R¹ is CN. In anotherembodiment, R¹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R¹ is CF₃.

In another embodiment, the invention features a compound of formulaI-D-3 and the attendant definitions, wherein R² is H. In anotherembodiment, R² is halogen. In another embodiment, R² is Cl. In anotherembodiment, R² is F. In another embodiment, R² is CN. In anotherembodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R² is CF₃. In anotherembodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replacedwith —O—. In another embodiment, R² is OCF₃. In another embodiment, R²is F, Cl, CN, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formulaI-D-3 and the attendant definitions, wherein R³ is H. In anotherembodiment, R³ is halogen. In another embodiment, R³ is Cl. In anotherembodiment, R³ is F. In another embodiment, R³ is CN. In anotherembodiment, R³ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R³ is t-butyl. In anotherembodiment, R³ is CF₃. In another embodiment, R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formulaI-D-3 and the attendant definitions, wherein R⁴ is H. In anotherembodiment, R⁴ is halogen. In another embodiment, R⁴ is CN. In anotherembodiment, R⁴ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R⁴ is CF₃.

In another embodiment, the invention features a compound of formulaI-D-3 and the attendant definitions, wherein R¹, R², R³, and R⁴ is H.

In another embodiment, the invention features a compound of formulaI-D-3 and the attendant definitions, R⁶ is halogen. In anotherembodiment, R⁶ is Cl. In another embodiment, R⁶ is F. In anotherembodiment, R⁶ is CN. In another embodiment, R⁶ is —X—R^(X). In anotherembodiment, R⁶ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁶ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁶ is CH₃. In another embodiment, R⁶ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁶ is OCH₃.

In another embodiment, the invention features a compound of formulaI-D-3 and the attendant definitions, wherein R⁷ is halogen. In anotherembodiment, R⁷ is Cl. In another embodiment, R⁷ is F. In anotherembodiment, R⁷ is CN. In another embodiment, R⁷ is —X—R^(X). In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. In anotherembodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formulaI-D-3 wherein R⁷ is —X—R^(X) wherein X is a bond and R^(X) is C₃-C₈cycloaliphatic and said C₃-C₈ cycloaliphatic is substituted with 0-3substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is a bond and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formulaI-D-3 and the attendant definitions, wherein R⁷ is —X—R^(X) wherein X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O— and R^(X)is C₃-C₈ cycloaliphatic and said C₃-C₈ cycloaliphatic is substitutedwith up 0-3 substituents selected from halogen and C₁-C₄ alkyl. Inanother embodiment, R⁷ is —X—R^(X) wherein X is OCH₂ and R^(X) iscyclopropyl.

In another embodiment, the invention features a compound of formulaI-D-3 and the attendant definitions, wherein ring A is selected from:

In another aspect, the invention provides a compound of formula I-D-4:

-   or a pharmaceutically acceptable salt thereof,-   wherein, independently for each occurrence:-   Y is C or N;-   m is an integer from 0 to 5 inclusive;-   W is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or —SO₂—;-   R^(W) is absent, H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, OCF₃, or a    3-6 membered saturated, partially unsaturated, or fully unsaturated    monocyclic ring having 0-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   R′ is C₁-C₆ alkyl;-   R¹ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen and wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R² is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R³ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁴ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁵ is halogen, CN, or —X—R^(X);-   R⁷ is halogen, CN, or —X—R^(X);-   X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—; and-   R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to two    non-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced    with —O— and said C₃-C₈ cycloaliphatic is substituted with 0-3    substituents selected from halogen and C₁-C₄ alkyl.

In one embodiment, the invention features a compound of formula I-D-4and the attendant definitions, wherein Y is C. In another embodiment, Yis N.

In another embodiment, the invention features a compound of formulaI-D-4 and the attendant definitions, wherein m is zero. In anotherembodiment, m is an integer from 1 to 5. In another embodiment, m is 1.In another embodiment, m is 2. In another embodiment, m is 3. In anotherembodiment, m is 4. In another embodiment, m is 5.

In another embodiment, the invention features a compound of formulaI-D-4 and the attendant definitions, wherein W is a bond and R^(W) ishalogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. In another embodiment, Wis a bond and R^(W) is halogen. In another embodiment, W is a bond andR^(W) is OH. In another embodiment, W is a bond and R^(W) is NH₂. Inanother embodiment, W is a bond and R^(W) is NHR′. In anotherembodiment, W is a bond and R^(W) is CN. In another embodiment, W is abond and R^(W) is CF₃. In another embodiment, W is a bond and R^(W) isOCF₃.

In another embodiment, the invention features a compound of formulaI-D-4 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. In another embodiment, Wis CH₃, CH₂CH₃, CH₂CH₂CH₃, or isopropyl. In another embodiment, W isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen,wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O—, —CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. Inanother embodiment, W is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, or O-isopropyl. Inanother embodiment, W is OCH₂CF₃, OCH₂CH₂CH₂CF₃, or OCHF₂. In anotherembodiment, W is OCH₂CH₂OCH₃, CH₂OH, OC(CH₃)₃, or CH₂CH₂OCH₃.

In another embodiment, the invention features a compound of formulaI-D-4 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂,CN, CF₃, or OCF₃. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or—SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO—, or —SO₂—, and R^(W) is H, OH, NH₂, or NHR′. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H. In another embodiment, W is C₁ alkylwherein one CH₂ unit of said C₁ alkyl is replaced with —CO— and R^(W) isOH. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁alkyl is replaced with —CO— and R^(W) is NH₂. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—and R^(W) is NHR′. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is H, OH, NH₂, orNHR′. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of saidC₁ alkyl is replaced with —SO₂— and R^(W) is H. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —SO₂—and R^(W) is OH. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is NH₂. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —SO₂— and R^(W) is NHR′.

In another embodiment, the invention features a compound of formulaI-D-4 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) absent. In another embodiment, W isC₂ alkyl wherein one CH₂ unit of said C₂ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is absent. In another embodiment, Wis C₂ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—,or —SO₂—, and R^(W) is absent.

In another embodiment, the invention features a compound of formulaI-D-4 and the attendant definitions, wherein W is a bond and R^(W) is a3-6 membered saturated, partially unsaturated, or fully unsaturatedmonocyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In another embodiment, W is a bond andR^(W) is a 5-membered aromatic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In another embodiment, W is abond and R^(W) is a 5-membered aromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In anotherembodiment, W is a bond and R^(W) is pyrrolyl, pyrazolyl, thiazolyl,thiadiazolyl, imidazolyl, oxazolyl, triazolyl, or tetrazolyl.

In another embodiment, the invention features a compound of formulaI-D-4 and the attendant definitions, wherein ring A₁ is selected from:

In another embodiment, the invention features a compound of formulaI-D-4 and the attendant definitions, wherein R¹ is H. In anotherembodiment, R¹ is halogen. In another embodiment, R¹ is CN. In anotherembodiment, R¹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R¹ is CF₃.

In another embodiment, the invention features a compound of formulaI-D-4 and the attendant definitions, wherein R² is H. In anotherembodiment, R² is halogen. In another embodiment, R² is Cl. In anotherembodiment, R² is F. In another embodiment, R² is CN. In anotherembodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R² is CF₃. In anotherembodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replacedwith —O—. In another embodiment, R² is OCF₃. In another embodiment, R²is F, Cl, CN, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formulaI-D-4 and the attendant definitions, wherein R³ is H. In anotherembodiment, R³ is halogen. In another embodiment, R³ is Cl. In anotherembodiment, R³ is F. In another embodiment, R³ is CN. In anotherembodiment, R³ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R³ is t-butyl. In anotherembodiment, R³ is CF₃. In another embodiment, R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formulaI-D-4 and the attendant definitions, wherein R⁴ is H. In anotherembodiment, R⁴ is halogen. In another embodiment, R⁴ is CN. In anotherembodiment, R⁴ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R⁴ is CF₃.

In another embodiment, the invention features a compound of formulaI-D-4 and the attendant definitions, wherein R¹, R², R³, and R⁴ is H.

In another embodiment, the invention features a compound of formulaI-D-4 and the attendant definitions, wherein R⁵ is halogen. In anotherembodiment, R⁵ is Cl. In another embodiment, R⁵ is F. In anotherembodiment, R⁵ is CN. In another embodiment, R⁵ is —X—R^(X). In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁵ is CH₃. In another embodiment, R⁵ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁵ is OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, or OCH(CH₃)₂. In another embodiment, R⁵ is OCH₃. In anotherembodiment, R⁵ is CH₂OH. In another embodiment, R⁵ is OCF₃. In anotherembodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formulaI-D-4 and the attendant definitions, wherein R⁷ is H. In anotherembodiment, R⁷ is halogen. In another embodiment, R⁷ is Cl. In anotherembodiment, R⁷ is F. In another embodiment, R⁷ is CN. In anotherembodiment, R⁷ is —X—R^(X). In another embodiment, R⁷ is —X—R^(X)wherein R^(X) is absent. In another embodiment, R⁷ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen. In another embodiment, R⁷ is CH₃, CH₂CH₃,CH₂CH₂CH₃ or isopropyl. In another embodiment, R⁷ is CF₃. In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen wherein twonon-adjacent CH₂ units of said C₁-C₆ alkyl are replaced with —O—. Inanother embodiment, R⁷ is OCH₂CH₂OCH₃. In another embodiment, R⁷ is—X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆alkyl is substituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆alkyl is replaced with —O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, OC(CH₃)₃, CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃,OCH₂CF₃, OCH₂CH₂CH₂CF₃, or OCHF₂.

In another embodiment, the invention features a compound of formulaI-D-4 wherein R⁷ is —X—R^(X) wherein X is a bond and R^(X) is C₃-C₈cycloaliphatic and said C₃-C₈ cycloaliphatic is substituted with 0-3substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is a bond and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formulaI-D-4 and the attendant definitions, wherein R⁷ is —X—R^(X) wherein X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O— and R^(X)is C₃-C₈ cycloaliphatic and said C₃-C₈ cycloaliphatic is substitutedwith up 0-3 substituents selected from halogen and C₁-C₄ alkyl. Inanother embodiment, R⁷ is —X—R^(X) wherein X is OCH₂ and R^(X) iscyclopropyl.

In another embodiment, the invention features a compound of formulaI-D-4 and the attendant definitions, wherein ring A is selected from:

In another aspect, the invention provides a compound of formula I-E:

-   or a pharmaceutically acceptable salt thereof,-   wherein, independently for each occurrence:-   Y is C or N;-   A₁ and A₂, together, form an 8-9 membered aromatic, bicyclic ring,    wherein each ring contains 0-4 heteroatoms independently selected    from nitrogen, oxygen, or sulfur;-   m is an integer from 0 to 5 inclusive;-   W is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or —SO₂—;-   R^(W) is absent, H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, OCF₃, or a    3-6 membered saturated, partially unsaturated, or fully unsaturated    monocyclic ring having 0-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   R′ is C₁-C₆ alkyl;-   R¹ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen and wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R² is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R³ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁴ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁵ is H, halogen, CN, or —X—R^(X);-   R^(5′) is H, halogen, CN, or —X—R^(X);-   R⁶ is H, halogen, CN, or —X—R^(X);-   R^(6′) is H, halogen, CN, or —X—R^(X);-   R⁷ is H, halogen, CN, or —X—R^(X);-   X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—; and-   R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to two    non-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced    with —O— and said C₃-C₈ cycloaliphatic is substituted with 0-3    substituents selected from halogen and C₁-C₄ alkyl.

In one embodiment, the invention features a compound of formula I-E andthe attendant definitions, wherein Y is C. In another embodiment, Y isN.

In another embodiment, the invention features a compound of formula I-Eand the attendant definitions, wherein A₁ is a 6 membered aromatic ringhaving 0-4 heteroatoms, independently selected from nitrogen, oxygen, orsulfur, and A₂ is a 5-membered aromatic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In anotherembodiment, A₁ is phenyl and A₂ is a 5-membered aromatic ring having 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur. Inanother embodiment, A₁ is phenyl and A₂ is pyrrolyl, pyrazolyl,thiazolyl, thiadiazolyl, imidazolyl, oxazolyl, or triazolyl.

In another embodiment, the invention features a compound of formula I-Eand the attendant definitions, wherein A₁ and A₂, together, are selectedfrom:

In another embodiment, the invention features a compound of formula I-Eand the attendant definitions, wherein m is zero. In another embodiment,m is an integer from 1 to 5. In another embodiment, m is 1. In anotherembodiment, m is 2. In another embodiment, m is 3. In anotherembodiment, m is 4. In another embodiment, m is 5.

In another embodiment, the invention features a compound of formula I-Eand the attendant definitions, wherein W is a bond and R^(W) is halogen,OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. In another embodiment, W is a bondand R^(W) is halogen. In another embodiment, W is a bond and R^(W) isOH. In another embodiment, W is a bond and R^(W) is NH₂. In anotherembodiment, W is a bond and R^(W) is NHR′. In another embodiment, W is abond and R^(W) is CN. In another embodiment, W is a bond and R^(W) isCF₃. In another embodiment, W is a bond and R^(W) is OCF₃.

In another embodiment, the invention features a compound of formula I-Eand the attendant definitions, wherein W is C₁-C₆ alkyl wherein saidC₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. In another embodiment, Wis CH₃, CH₂CH₃, CH₂CH₂CH₃, or isopropyl. In another embodiment, W isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen,wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O—, —CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. Inanother embodiment, W is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, or O-isopropyl. Inanother embodiment, W is OCH₂CF₃, OCH₂CH₂CH₂CF₃, or OCHF₂. In anotherembodiment, W is OCH₂CH₂OCH₃, CH₂OH, OC(CH₃)₃, or CH₂CH₂OCH₃.

In another embodiment, the invention features a compound of formula I-Eand the attendant definitions, wherein W is C₁-C₆ alkyl wherein saidC₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂,CN, CF₃, or OCF₃. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or—SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO—, or —SO₂—, and R^(W) is H, OH, NH₂, or NHR′. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H. In another embodiment, W is C₁ alkylwherein one CH₂ unit of said C₁ alkyl is replaced with —CO— and R^(W) isOH. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁alkyl is replaced with —CO— and R^(W) is NH₂. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—and R^(W) is NHR′. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is H, OH, NH₂, orNHR′. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of saidC₁ alkyl is replaced with —SO₂— and R^(W) is H. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —SO₂—and R^(W) is OH. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is NH₂. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —SO₂— and R^(W) is NHR′.

In another embodiment, the invention features a compound of formula I-Eand the attendant definitions, wherein W is C₁-C₆ alkyl wherein saidC₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) absent. In another embodiment, W isC₂ alkyl wherein one CH₂ unit of said C₂ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is absent. In another embodiment, Wis C₂ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—,or —SO₂—, and R^(W) is absent.

In another embodiment, the invention features a compound of formula I-Eand the attendant definitions, A₁ and A₂, together with WR^(W), areselected from:

In another embodiment, the invention features a compound of formula I-Eand the attendant definitions, wherein R¹ is H. In another embodiment,R¹ is halogen. In another embodiment, R¹ is CN. In another embodiment,R¹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen. In another embodiment, R¹ is CF₃.

In another embodiment, the invention features a compound of formula I-Eand the attendant definitions, wherein R² is H. In another embodiment,R² is halogen. In another embodiment, R² is Cl. In another embodiment,R² is F. In another embodiment, R² is CN. In another embodiment, R² isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R² is CF₃. In another embodiment, R² is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen wherein one CH₂unit of said C₁-C₆ alkyl is replaced with —O—. In another embodiment, R²is OCF₃. In another embodiment, R² is F, Cl, CN, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formula I-Eand the attendant definitions, wherein R³ is H. In another embodiment,R³ is halogen. In another embodiment, R³ is Cl. In another embodiment,R³ is F. In another embodiment, R³ is CN. In another embodiment, R³ isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R³ is t-butyl. In another embodiment, R³ is CF₃. Inanother embodiment, R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formula I-Eand the attendant definitions, wherein R⁴ is H. In another embodiment,R⁴ is halogen. In another embodiment, R⁴ is CN. In another embodiment,R⁴ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen. In another embodiment, R⁴ is CF₃.

In another embodiment, the invention features a compound of formula I-Eand the attendant definitions, wherein R¹, R², R³, and R⁴ is H.

In another embodiment, the invention features a compound of formula I-Eand the attendant definitions, wherein R⁵ is H. In another embodiment,R⁵ is halogen. In another embodiment, R⁵ is Cl. In another embodiment,R⁵ is F. In another embodiment, R⁵ is CN. In another embodiment, R⁵ is—X—R^(X). In another embodiment, R⁵ is —X—R^(X) wherein R^(X) is absent.In another embodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R⁵ is CH₃. In another embodiment, R⁵ is —X—R^(X)wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁵ is OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, or OCH(CH₃)₂. In another embodiment, R⁵ is OCH₃. In anotherembodiment, R⁵ is CH₂OH. In another embodiment, R⁵ is OCF₃. In anotherembodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula I-Eand the attendant definitions, wherein R^(5′) is H. In anotherembodiment, R^(5′) is halogen. In another embodiment, R^(5′) is Cl. Inanother embodiment, R^(5′) is F. In another embodiment, R^(5′) is CN. Inanother embodiment, R^(5′) is —X—R^(X). In another embodiment, R^(5′) is—X—R^(X) wherein R^(X) is absent. In another embodiment, R^(5′) is—X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆alkyl is substituted with 0-6 halogen. In another embodiment, R^(5′) isCH₃. In another embodiment, R^(5′) is —X—R^(X) wherein R^(X) is absentand X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O—.In another embodiment, R^(5′) is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, orOCH(CH₃)₂. In another embodiment, R^(5′) is OCH₃. In another embodiment,R^(5′) is CH₂OH. In another embodiment, R^(5′) is OCF₃. In anotherembodiment, R^(5′) is OCHF₂.

In another embodiment, the invention features a compound of formula I-Eand the attendant definitions, R⁶ is H. In another embodiment, R⁶ ishalogen. In another embodiment, R⁶ is Cl. In another embodiment, R⁶ isF. In another embodiment, R⁶ is CN. In another embodiment, R⁶ is—X—R^(X). In another embodiment, R⁶ is —X—R^(X) wherein R^(X) is absent.In another embodiment, R⁶ is —X—R^(X) wherein R^(X) is absent and X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R⁶ is CH₃. In another embodiment, R⁶ is —X—R^(X)wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁶ is OCH₃.

In another embodiment, the invention features a compound of formula I-Eand the attendant definitions, wherein R^(6′) is H. In anotherembodiment, R^(6′) is halogen. In another embodiment, R^(6′) is Cl. Inanother embodiment, R^(6′) is F. In another embodiment, R^(6′) is CN. Inanother embodiment, R^(6′) is —X—R^(X). In another embodiment, R^(6′) is—X—R^(X) wherein R^(X) is absent. In another embodiment, R^(6′) is—X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆alkyl is substituted with 0-6 halogen. In another embodiment, R^(6′) isCH₃. In another embodiment, R^(6′) is —X—R^(X) wherein R^(X) is absentand X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O—.In another embodiment, R^(6′) is OCH₃.

In another embodiment, the invention features a compound of formula I-Eand the attendant definitions, wherein R⁷ is H. In another embodiment,R⁷ is halogen. In another embodiment, R⁷ is Cl. In another embodiment,R⁷ is F. In another embodiment, R⁷ is CN. In another embodiment, R⁷ is—X—R^(X). In another embodiment, R⁷ is —X—R^(X) wherein R^(X) is absent.In another embodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. Inanother embodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X)wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formula I-Ewherein R⁷ is —X—R^(X) wherein X is a bond and R^(X) is C₃-C₈cycloaliphatic and said C₃-C₈ cycloaliphatic is substituted with 0-3substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is a bond and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Eand the attendant definitions, wherein R⁷ is —X—R^(X) wherein X is C₁-C₆alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen whereinone CH₂ unit of said C₁-C₆ alkyl is replaced with —O— and R^(X) is C₃-C₈cycloaliphatic and said C₃-C₈ cycloaliphatic is substituted with up 0-3substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is OCH₂ and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Eand the attendant definitions, wherein ring A is selected from:

In another embodiment ring A is selected from:

In another embodiment, the invention features a compound of formula I-Eand the attendant definitions, wherein R¹, R², R³ and R⁴ are H.

In another embodiment, the invention features a compound of formula I-Eand the attendant definitions, wherein R⁵ and R⁷ are each independentlyhalogen, or —X—R^(X) and R^(5′), R⁶, and R^(6′) are each hydrogen. Inanother embodiment, R⁵ and R⁷ are each independently F, Cl, CH₃, OCF₃,or OCH₃.

In another aspect, the invention provides a compound of formula I-F:

-   or a pharmaceutically acceptable salt thereof,-   wherein, independently for each occurrence:-   Y is C or N;-   m is an integer from 0 to 5 inclusive;-   W is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or —SO₂—;-   R^(W) is absent, H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, OCF₃, or a    3-6 membered saturated, partially unsaturated, or fully unsaturated    monocyclic ring having 0-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   R′ is C₁-C₆ alkyl;-   R¹ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen and wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R² is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R³ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁴ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁵ is H, halogen, CN, or —X—R^(X);-   R^(5′) is H, halogen, CN, or —X—R^(X);-   R⁶ is H, halogen, CN, or —X—R^(X);-   R^(6′) is H, halogen, CN, or —X—R^(X);-   R⁷ is H, halogen, CN, or —X—R^(X);-   X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—; and-   R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to two    non-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced    with —O— and said C₃-C₈ cycloaliphatic is substituted with 0-3    substituents selected from halogen and C₁-C₄ alkyl.

In one embodiment, the invention features a compound of formula I-F andthe attendant definitions, wherein Y is C. In another embodiment, Y isN.

In another embodiment, the invention features a compound of formula I-Fand the attendant definitions, wherein m is zero. In another embodiment,m is an integer from 1 to 5. In another embodiment, m is 1. In anotherembodiment, m is 2. In another embodiment, m is 3. In anotherembodiment, m is 4. In another embodiment, m is 5.

In another embodiment, the invention features a compound of formula I-Fand the attendant definitions, wherein W is a bond and R^(W) is halogen,OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. In another embodiment, W is a bondand R^(W) is halogen. In another embodiment, W is a bond and R^(W) isOH. In another embodiment, W is a bond and R^(W) is NH₂. In anotherembodiment, W is a bond and R^(W) is NHR′. In another embodiment, W is abond and R^(W) is CN. In another embodiment, W is a bond and R^(W) isCF₃. In another embodiment, W is a bond and R^(W) is OCF₃.

In another embodiment, the invention features a compound of formula I-Fand the attendant definitions, wherein W is C₁-C₆ alkyl wherein saidC₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. In another embodiment, Wis CH₃, CH₂CH₃, CH₂CH₂CH₃, or isopropyl. In another embodiment, W isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen,wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O—, —CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. Inanother embodiment, W is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, or O-isopropyl. Inanother embodiment, W is OCH₂CF₃, OCH₂CH₂CH₂CF₃, or OCHF₂. In anotherembodiment, W is OCH₂CH₂OCH₃, CH₂OH, OC(CH₃)₃, or CH₂CH₂OCH₃.

In another embodiment, the invention features a compound of formula I-Fand the attendant definitions, wherein W is C₁-C₆ alkyl wherein saidC₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂,CN, CF₃, or OCF₃. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or—SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO—, or —SO₂—, and R^(W) is H, OH, NH₂, or NHR′. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H. In another embodiment, W is C₁ alkylwherein one CH₂ unit of said C₁ alkyl is replaced with —CO— and R^(W) isOH. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁alkyl is replaced with —CO— and R^(W) is NH₂. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—and R^(W) is NHR′. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is H, OH, NH₂, orNHR′. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of saidC₁ alkyl is replaced with —SO₂— and R^(W) is H. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —SO₂—and R^(W) is OH. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is NH₂. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —SO₂— and R^(W) is NHR′.

In another embodiment, the invention features a compound of formula I-Fand the attendant definitions, wherein W is C₁-C₆ alkyl wherein saidC₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) absent. In another embodiment, W isC₂ alkyl wherein one CH₂ unit of said C₂ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is absent. In another embodiment, Wis C₂ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—,or —SO₂—, and R^(W) is absent.

In another embodiment, the invention features a compound of formula I-Fand the attendant definitions, wherein A₁ and A₂, together with WR^(W),are selected from:

In another embodiment, the invention features a compound of formula I-Fand the attendant definitions, wherein R¹ is H. In another embodiment,R¹ is halogen. In another embodiment, R¹ is CN. In another embodiment,R¹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen. In another embodiment, R¹ is CF₃.

In another embodiment, the invention features a compound of formula I-Fand the attendant definitions, wherein R² is H. In another embodiment,R² is halogen. In another embodiment, R² is Cl. In another embodiment,R² is F. In another embodiment, R² is CN. In another embodiment, R² isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R² is CF₃. In another embodiment, R² is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen wherein one CH₂unit of said C₁-C₆ alkyl is replaced with —O—. In another embodiment, R²is OCF₃. In another embodiment, R² is F, Cl, CN, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formula I-Fand the attendant definitions, wherein R³ is H. In another embodiment,R³ is halogen. In another embodiment, R³ is Cl. In another embodiment,R³ is F. In another embodiment, R³ is CN. In another embodiment, R³ isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R³ is t-butyl. In another embodiment, R³ is CF₃. Inanother embodiment, R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formula I-Fand the attendant definitions, wherein R⁴ is H. In another embodiment,R⁴ is halogen. In another embodiment, R⁴ is CN. In another embodiment,R⁴ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen. In another embodiment, R⁴ is CF₃.

In another embodiment, the invention features a compound of formula I-Fand the attendant definitions, wherein R¹, R², R³, and R⁴ is H.

In another embodiment, the invention features a compound of formula I-Fand the attendant definitions, wherein R⁵ is H. In another embodiment,R⁵ is halogen. In another embodiment, R⁵ is Cl. In another embodiment,R⁵ is F. In another embodiment, R⁵ is CN. In another embodiment, R⁵ is—X—R^(X). In another embodiment, R⁵ is —X—R^(X) wherein R^(X) is absent.In another embodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R⁵ is CH₃. In another embodiment, R⁵ is —X—R^(X)wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁵ is OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, or OCH(CH₃)₂. In another embodiment, R⁵ is OCH₃. In anotherembodiment, R⁵ is CH₂OH. In another embodiment, R⁵ is OCF₃. In anotherembodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formula I-Fand the attendant definitions, wherein R^(5′) is H. In anotherembodiment, R^(5′) is halogen. In another embodiment, R^(5′) is Cl. Inanother embodiment, R^(5′) is F. In another embodiment, R^(5′) is CN. Inanother embodiment, R^(5′) is —X—R^(X). In another embodiment, R^(5′) is—X—R^(X) wherein R^(X) is absent. In another embodiment, R^(5′) is—X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆alkyl is substituted with 0-6 halogen. In another embodiment, R^(5′) isCH₃. In another embodiment, R^(5′) is —X—R^(X) wherein R^(X) is absentand X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O—.In another embodiment, R^(5′) is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, orOCH(CH₃)₂. In another embodiment, R^(5′) is OCH₃. In another embodiment,R^(5′) is CH₂OH. In another embodiment, R^(5′) is OCF₃. In anotherembodiment, R^(5′) is OCHF₂.

In another embodiment, the invention features a compound of formula I-Fand the attendant definitions, R⁶ is H. In another embodiment, R⁶ ishalogen. In another embodiment, R⁶ is Cl. In another embodiment, R⁶ isF. In another embodiment, R⁶ is CN. In another embodiment, R⁶ is—X—R^(X). In another embodiment, R⁶ is —X—R^(X) wherein R^(X) is absent.In another embodiment, R⁶ is —X—R^(X) wherein R^(X) is absent and X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R⁶ is CH₃. In another embodiment, R⁶ is —X—R^(X)wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁶ is OCH₃.

In another embodiment, the invention features a compound of formula I-Fand the attendant definitions, wherein R^(6′) is H. In anotherembodiment, R^(6′) is halogen. In another embodiment, R^(6′) is Cl. Inanother embodiment, R^(6′) is F. In another embodiment, R^(6′) is CN. Inanother embodiment, R^(6′) is —X—R^(X). In another embodiment, R^(6′) is—X—R^(X) wherein R^(X) is absent. In another embodiment, R^(6′) is—X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆alkyl is substituted with 0-6 halogen. In another embodiment, R^(6′) isCH₃. In another embodiment, R^(6′) is —X—R^(X) wherein R^(X) is absentand X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O—.In another embodiment, R^(6′) is OCH₃.

In another embodiment, the invention features a compound of formula I-Fand the attendant definitions, wherein R⁷ is H. In another embodiment,R⁷ is halogen. In another embodiment, R⁷ is Cl. In another embodiment,R⁷ is F. In another embodiment, R⁷ is CN. In another embodiment, R⁷ is—X—R^(X). In another embodiment, R⁷ is —X—R^(X) wherein R^(X) is absent.In another embodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen. Inanother embodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. Inanother embodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X)wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formula I-Fwherein R⁷ is —X—R^(X) wherein X is a bond and R^(X) is C₃-C₈cycloaliphatic and said C₃-C₈ cycloaliphatic is substituted with 0-3substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is a bond and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Fand the attendant definitions, wherein R⁷ is —X—R^(X) wherein X is C₁-C₆alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen whereinone CH₂ unit of said C₁-C₆ alkyl is replaced with —O— and R^(X) is C₃-C₈cycloaliphatic and said C₃-C₈ cycloaliphatic is substituted with up 0-3substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is OCH₂ and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Fand the attendant definitions, wherein ring A is selected from:

In another aspect, the invention provides a compound of formula I-F-1:

-   or a pharmaceutically acceptable salt thereof,-   wherein, independently for each occurrence:-   Y is C or N;-   m is an integer from 0 to 5 inclusive;-   W is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or —SO₂—;-   R^(W) is absent, H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, OCF₃, or a    3-6 membered saturated, partially unsaturated, or fully unsaturated    monocyclic ring having 0-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   R′ is C₁-C₆ alkyl;-   R¹ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen and wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R² is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R³ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁴ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁵ is halogen, CN, or —X—R^(X);-   X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—; and-   R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to two    non-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced    with —O— and said C₃-C₈ cycloaliphatic is substituted with 0-3    substituents selected from halogen and C₁-C₄ alkyl.

In one embodiment, the invention features a compound of formula I-F-1and the attendant definitions, wherein Y is C. In another embodiment, Yis N.

In another embodiment, the invention features a compound of formulaI-F-1 and the attendant definitions, wherein m is zero. In anotherembodiment, m is an integer from 1 to 5. In another embodiment, m is 1.In another embodiment, m is 2. In another embodiment, m is 3. In anotherembodiment, m is 4. In another embodiment, m is 5.

In another embodiment, the invention features a compound of formulaI-F-1 and the attendant definitions, wherein W is a bond and R^(W) ishalogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. In another embodiment, Wis a bond and R^(W) is halogen. In another embodiment, W is a bond andR^(W) is OH. In another embodiment, W is a bond and R^(W) is NH₂. Inanother embodiment, W is a bond and R^(W) is NHR′. In anotherembodiment, W is a bond and R^(W) is CN. In another embodiment, W is abond and R^(W) is CF₃. In another embodiment, W is a bond and R^(W) isOCF₃.

In another embodiment, the invention features a compound of formulaI-F-1 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. In another embodiment, Wis CH₃, CH₂CH₃, CH₂CH₂CH₃, or isopropyl. In another embodiment, W isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen,wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O—, —CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. Inanother embodiment, W is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, or O-isopropyl. Inanother embodiment, W is OCH₂CF₃, OCH₂CH₂CH₂CF₃, or OCHF₂. In anotherembodiment, W is OCH₂CH₂OCH₃, CH₂OH, OC(CH₃)₃, or CH₂CH₂OCH₃.

In another embodiment, the invention features a compound of formulaI-F-1 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂,CN, CF₃, or OCF₃. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or—SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO—, or —SO₂—, and R^(W) is H, OH, NH₂, or NHR′. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H. In another embodiment, W is C₁ alkylwherein one CH₂ unit of said C₁ alkyl is replaced with —CO— and R^(W) isOH. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁alkyl is replaced with —CO— and R^(W) is NH₂. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—and R^(W) is NHR′. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is H, OH, NH₂, orNHR′. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of saidC₁ alkyl is replaced with —SO₂— and R^(W) is H. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —SO₂—and R^(W) is OH. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is NH₂. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —SO₂— and R^(W) is NHR′.

In another embodiment, the invention features a compound of formulaI-F-1 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) absent. In another embodiment, W isC₂ alkyl wherein one CH₂ unit of said C₂ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is absent. In another embodiment, Wis C₂ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—,or —SO₂—, and R^(W) is absent.

In another embodiment, the invention features a compound of formulaI-F-1 and the attendant definitions, wherein A₁ and A₂, together withWR^(W), are selected from:

In another embodiment, the invention features a compound of formulaI-F-1 and the attendant definitions, wherein R¹ is H. In anotherembodiment, R¹ is halogen. In another embodiment, R¹ is CN. In anotherembodiment, R¹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R¹ is CF₃.

In another embodiment, the invention features a compound of formulaI-F-1 and the attendant definitions, wherein R² is H. In anotherembodiment, R² is halogen. In another embodiment, R² is Cl. In anotherembodiment, R² is F. In another embodiment, R² is CN. In anotherembodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R² is CF₃. In anotherembodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replacedwith —O—. In another embodiment, R² is OCF₃. In another embodiment, R²is F, Cl, CN, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formulaI-F-1 and the attendant definitions, wherein R³ is H. In anotherembodiment, R³ is halogen. In another embodiment, R³ is Cl. In anotherembodiment, R³ is F. In another embodiment, R³ is CN. In anotherembodiment, R³ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R³ is t-butyl. In anotherembodiment, R³ is CF₃. In another embodiment, R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formulaI-F-1 and the attendant definitions, wherein R⁴ is H. In anotherembodiment, R⁴ is halogen. In another embodiment, R⁴ is CN. In anotherembodiment, R⁴ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R⁴ is CF₃.

In another embodiment, the invention features a compound of formulaI-F-1 and the attendant definitions, wherein R¹, R², R³, and R⁴ is H.

In another embodiment, the invention features a compound of formulaI-F-1 and the attendant definitions, wherein R⁵ is halogen. In anotherembodiment, R⁵ is Cl. In another embodiment, R⁵ is F. In anotherembodiment, R⁵ is CN. In another embodiment, R⁵ is —X—R^(X). In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁵ is CH₃. In another embodiment, R⁵ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁵ is OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, or OCH(CH₃)₂. In another embodiment, R⁵ is OCH₃. In anotherembodiment, R⁵ is CH₂OH. In another embodiment, R⁵ is OCF₃. In anotherembodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formulaI-F-1 and the attendant definitions, wherein ring A is selected from:

In another aspect, the invention provides a compound of formula I-F-2:

-   or a pharmaceutically acceptable salt thereof,-   wherein, independently for each occurrence:-   Y is C or N;-   m is an integer from 0 to 5 inclusive;-   W is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or —SO₂—;-   R^(W) is absent, H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, OCF₃, or a    3-6 membered saturated, partially unsaturated, or fully unsaturated    monocyclic ring having 0-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   R′ is C₁-C₆ alkyl;-   R¹ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen and wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R² is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R³ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁴ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁷ is halogen, CN, or —X—R^(X);-   X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—; and-   R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to two    non-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced    with —O— and said C₃-C₈ cycloaliphatic is substituted with 0-3    substituents selected from halogen and C₁-C₄ alkyl.

In one embodiment, the invention features a compound of formula I-F-2and the attendant definitions, wherein Y is C. In another embodiment, Yis N.

In another embodiment, the invention features a compound of formulaI-F-2 and the attendant definitions, wherein m is zero. In anotherembodiment, m is an integer from 1 to 5. In another embodiment, m is 1.In another embodiment, m is 2. In another embodiment, m is 3. In anotherembodiment, m is 4. In another embodiment, m is 5.

In another embodiment, the invention features a compound of formulaI-F-2 and the attendant definitions, wherein W is a bond and R^(W) ishalogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. In another embodiment, Wis a bond and R^(W) is halogen. In another embodiment, W is a bond andR^(W) is OH. In another embodiment, W is a bond and R^(W) is NH₂. Inanother embodiment, W is a bond and R^(W) is NHR′. In anotherembodiment, W is a bond and R^(W) is CN. In another embodiment, W is abond and R^(W) is CF₃. In another embodiment, W is a bond and R^(W) isOCF₃.

In another embodiment, the invention features a compound of formulaI-F-2 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. In another embodiment, Wis CH₃, CH₂CH₃, CH₂CH₂CH₃, or isopropyl. In another embodiment, W isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen,wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O—, —CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. Inanother embodiment, W is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, or O-isopropyl. Inanother embodiment, W is OCH₂CF₃, OCH₂CH₂CH₂CF₃, or OCHF₂. In anotherembodiment, W is OCH₂CH₂OCH₃, CH₂OH, OC(CH₃)₃, or CH₂CH₂OCH₃.

In another embodiment, the invention features a compound of formulaI-F-2 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂,CN, CF₃, or OCF₃. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or—SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO—, or —SO₂—, and R^(W) is H, OH, NH₂, or NHR′. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H. In another embodiment, W is C₁ alkylwherein one CH₂ unit of said C₁ alkyl is replaced with —CO— and R^(W) isOH. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁alkyl is replaced with —CO— and R^(W) is NH₂. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—and R^(W) is NHR′. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is H, OH, NH₂, orNHR′. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of saidC₁ alkyl is replaced with —SO₂— and R^(W) is H. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —SO₂—and R^(W) is OH. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is NH₂. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —SO₂— and R^(W) is NHR′.

In another embodiment, the invention features a compound of formulaI-F-2 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) absent. In another embodiment, W isC₂ alkyl wherein one CH₂ unit of said C₂ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is absent. In another embodiment, Wis C₂ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—,or —SO₂—, and R^(W) is absent.

In another embodiment, the invention features a compound of formulaI-F-2 and the attendant definitions, wherein A₁ and A₂, together withWR^(W), are selected from:

In another embodiment, the invention features a compound of formulaI-F-2 and the attendant definitions, wherein R¹ is H. In anotherembodiment, R¹ is halogen. In another embodiment, R¹ is CN. In anotherembodiment, R¹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R¹ is CF₃.

In another embodiment, the invention features a compound of formulaI-F-2 and the attendant definitions, wherein R² is H. In anotherembodiment, R² is halogen. In another embodiment, R² is Cl. In anotherembodiment, R² is F. In another embodiment, R² is CN. In anotherembodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R² is CF₃. In anotherembodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replacedwith —O—. In another embodiment, R² is OCF₃. In another embodiment, R²is F, Cl, CN, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formulaI-F-2 and the attendant definitions, wherein R³ is H. In anotherembodiment, R³ is halogen. In another embodiment, R³ is Cl. In anotherembodiment, R³ is F. In another embodiment, R³ is CN. In anotherembodiment, R³ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R³ is t-butyl. In anotherembodiment, R³ is CF₃. In another embodiment, R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formulaI-F-2 and the attendant definitions, wherein R⁴ is H. In anotherembodiment, R⁴ is halogen. In another embodiment, R⁴ is CN. In anotherembodiment, R⁴ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R⁴ is CF₃.

In another embodiment, the invention features a compound of formulaI-F-2 and the attendant definitions, wherein R¹, R², R³, and R⁴ is H.

In another embodiment, the invention features a compound of formulaI-F-2 and the attendant definitions, wherein R⁷ is halogen. In anotherembodiment, R⁷ is Cl. In another embodiment, R⁷ is F. In anotherembodiment, R⁷ is CN. In another embodiment, R⁷ is —X—R^(X). In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. In anotherembodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formulaI-F-2 wherein R⁷ is —X—R^(X) wherein X is a bond and R^(X) is C₃-C₈cycloaliphatic and said C₃-C₈ cycloaliphatic is substituted with 0-3substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is a bond and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formulaI-F-2 and the attendant definitions, wherein R⁷ is —X—R^(X) wherein X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O— and R^(X)is C₃-C₈ cycloaliphatic and said C₃-C₈ cycloaliphatic is substitutedwith up 0-3 substituents selected from halogen and C₁-C₄ alkyl. Inanother embodiment, R⁷ is —X—R^(X) wherein X is OCH₂ and R^(X) iscyclopropyl.

In another embodiment, the invention features a compound of formulaI-F-2 and the attendant definitions, wherein ring A is selected from:

In another aspect, the invention provides a compound of formula I-F-3:

-   or a pharmaceutically acceptable salt thereof,-   wherein, independently for each occurrence:-   Y is C or N;-   m is an integer from 0 to 5 inclusive;-   W is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or —SO₂—;-   R^(W) is absent, H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, OCF₃, or a    3-6 membered saturated, partially unsaturated, or fully unsaturated    monocyclic ring having 0-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   R′ is C₁-C₆ alkyl;-   R¹ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen and wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R² is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R³ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁴ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁶ is halogen, CN, or —X—R^(X);-   R⁷ is halogen, CN, or —X—R^(X);-   X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—; and-   R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to two    non-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced    with —O— and said C₃-C₈ cycloaliphatic is substituted with 0-3    substituents selected from halogen and C₁-C₄ alkyl.

In one embodiment, the invention features a compound of formula I-F-3and the attendant definitions, wherein Y is C. In another embodiment, Yis N.

In another embodiment, the invention features a compound of formulaI-F-3 and the attendant definitions, wherein m is zero. In anotherembodiment, m is an integer from 1 to 5. In another embodiment, m is 1.In another embodiment, m is 2. In another embodiment, m is 3. In anotherembodiment, m is 4. In another embodiment, m is 5.

In another embodiment, the invention features a compound of formulaI-F-3 and the attendant definitions, wherein W is a bond and R^(W) ishalogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. In another embodiment, Wis a bond and R^(W) is halogen. In another embodiment, W is a bond andR^(W) is OH. In another embodiment, W is a bond and R^(W) is NH₂. Inanother embodiment, W is a bond and R^(W) is NHR′. In anotherembodiment, W is a bond and R^(W) is CN. In another embodiment, W is abond and R^(W) is CF₃. In another embodiment, W is a bond and R^(W) isOCF₃.

In another embodiment, the invention features a compound of formulaI-F-3 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. In another embodiment, Wis CH₃, CH₂CH₃, CH₂CH₂CH₃, or isopropyl. In another embodiment, W isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen,wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O—, —CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. Inanother embodiment, W is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, or O-isopropyl. Inanother embodiment, W is OCH₂CF₃, OCH₂CH₂CH₂CF₃, or OCHF₂. In anotherembodiment, W is OCH₂CH₂OCH₃, CH₂OH, OC(CH₃)₃, or CH₂CH₂OCH₃.

In another embodiment, the invention features a compound of formulaI-F-3 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂,CN, CF₃, or OCF₃. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or—SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO—, or —SO₂—, and R^(W) is H, OH, NH₂, or NHR′. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H. In another embodiment, W is C₁ alkylwherein one CH₂ unit of said C₁ alkyl is replaced with —CO— and R^(W) isOH. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁alkyl is replaced with —CO— and R^(W) is NH₂. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—and R^(W) is NHR′. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is H, OH, NH₂, orNHR′. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of saidC₁ alkyl is replaced with —SO₂— and R^(W) is H. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —SO₂—and R^(W) is OH. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is NH₂. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —SO₂— and R^(W) is NHR′.

In another embodiment, the invention features a compound of formulaI-F-3 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) absent. In another embodiment, W isC₂ alkyl wherein one CH₂ unit of said C₂ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is absent. In another embodiment, Wis C₂ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—,or —SO₂—, and R^(W) is absent.

In another embodiment, the invention features a compound of formulaI-F-3 and the attendant definitions, wherein A₁ and A₂, together withWR^(W), are selected from:

In another embodiment, the invention features a compound of formulaI-F-3 and the attendant definitions, wherein R¹ is H. In anotherembodiment, R¹ is halogen. In another embodiment, R¹ is CN. In anotherembodiment, R¹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R¹ is CF₃.

In another embodiment, the invention features a compound of formulaI-F-3 and the attendant definitions, wherein R² is H. In anotherembodiment, R² is halogen. In another embodiment, R² is Cl. In anotherembodiment, R² is F. In another embodiment, R² is CN. In anotherembodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R² is CF₃. In anotherembodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replacedwith —O—. In another embodiment, R² is OCF₃. In another embodiment, R²is F, Cl, CN, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formulaI-F-3 and the attendant definitions, wherein R³ is H. In anotherembodiment, R³ is halogen. In another embodiment, R³ is Cl. In anotherembodiment, R³ is F. In another embodiment, R³ is CN. In anotherembodiment, R³ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R³ is t-butyl. In anotherembodiment, R³ is CF₃. In another embodiment, R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formulaI-F-3 and the attendant definitions, wherein R⁴ is H. In anotherembodiment, R⁴ is halogen. In another embodiment, R⁴ is CN. In anotherembodiment, R⁴ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R⁴ is CF₃.

In another embodiment, the invention features a compound of formulaI-F-3 and the attendant definitions, wherein R¹, R², R³, and R⁴ is H.

In another embodiment, the invention features a compound of formulaI-F-3 and the attendant definitions, R⁶ is halogen. In anotherembodiment, R⁶ is Cl. In another embodiment, R⁶ is F. In anotherembodiment, R⁶ is CN. In another embodiment, R⁶ is —X—R^(X). In anotherembodiment, R⁶ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁶ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁶ is CH₃. In another embodiment, R⁶ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁶ is OCH₃.

In another embodiment, the invention features a compound of formulaI-F-3 and the attendant definitions, wherein R⁷ is halogen. In anotherembodiment, R⁷ is Cl. In another embodiment, R⁷ is F. In anotherembodiment, R⁷ is CN. In another embodiment, R⁷ is —X—R^(X). In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁷ is CH₃, CH₂CH₃, CH₂CH₂CH₃ or isopropyl. In anotherembodiment, R⁷ is CF₃. In another embodiment, R⁷ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein two non-adjacent CH₂ units of saidC₁-C₆ alkyl are replaced with —O—. In another embodiment, R⁷ isOCH₂CH₂OCH₃. In another embodiment, R⁷ is —X—R^(X) wherein R^(X) isabsent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replaced with—O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OC(CH₃)₃,CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃, OCH₂CF₃, OCH₂CH₂CH₂CF₃,or OCHF₂.

In another embodiment, the invention features a compound of formulaI-F-3 wherein R⁷ is —X—R^(X) wherein X is a bond and R^(X) is C₃-C₈cycloaliphatic and said C₃-C₈ cycloaliphatic is substituted with 0-3substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is a bond and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formulaI-F-3 and the attendant definitions, wherein R⁷ is —X—R^(X) wherein X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O— and R^(X)is C₃-C₈ cycloaliphatic and said C₃-C₈ cycloaliphatic is substitutedwith up 0-3 substituents selected from halogen and C₁-C₄ alkyl. Inanother embodiment, R⁷ is —X—R^(X) wherein X is OCH₂ and R^(X) iscyclopropyl.

In another embodiment, the invention features a compound of formulaI-F-3 and the attendant definitions, wherein ring A is selected from:

In another aspect, the invention provides a compound of formula I-F-4:

-   or a pharmaceutically acceptable salt thereof,-   wherein, independently for each occurrence:-   Y is C or N;-   m is an integer from 0 to 5 inclusive;-   W is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or —SO₂—;-   R^(W) is absent, H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, OCF₃, or a    3-6 membered saturated, partially unsaturated, or fully unsaturated    monocyclic ring having 0-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   R′ is C₁-C₆ alkyl;-   R¹ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen and wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R² is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R³ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁴ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen, wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁵ is halogen, CN, or —X—R^(X);-   R⁷ is halogen, CN, or —X—R^(X);-   X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted    with 0-6 halogen, wherein up to two non-adjacent CH₂ units of said    C₁-C₆ alkyl may be replaced with —O—; and-   R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to two    non-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced    with —O— and said C₃-C₈ cycloaliphatic is substituted with 0-3    substituents selected from halogen and C₁-C₄ alkyl.

In one embodiment, the invention features a compound of formula I-F-4and the attendant definitions, wherein Y is C. In another embodiment, Yis N.

In another embodiment, the invention features a compound of formulaI-F-4 and the attendant definitions, wherein m is zero. In anotherembodiment, m is an integer from 1 to 5. In another embodiment, m is 1.In another embodiment, m is 2. In another embodiment, m is 3. In anotherembodiment, m is 4. In another embodiment, m is 5.

In another embodiment, the invention features a compound of formulaI-F-4 and the attendant definitions, wherein W is a bond and R^(W) ishalogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. In another embodiment, Wis a bond and R^(W) is halogen. In another embodiment, W is a bond andR^(W) is OH. In another embodiment, W is a bond and R^(W) is NH₂. Inanother embodiment, W is a bond and R^(W) is NHR′. In anotherembodiment, W is a bond and R^(W) is CN. In another embodiment, W is abond and R^(W) is CF₃. In another embodiment, W is a bond and R^(W) isOCF₃.

In another embodiment, the invention features a compound of formulaI-F-4 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. In another embodiment, Wis CH₃, CH₂CH₃, CH₂CH₂CH₃, or isopropyl. In another embodiment, W isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen,wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O—, —CO—, —S—, —SO—, or —SO₂—; and R^(W) is absent. Inanother embodiment, W is OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, or O-isopropyl. Inanother embodiment, W is OCH₂CF₃, OCH₂CH₂CH₂CF₃, or OCHF₂. In anotherembodiment, W is OCH₂CH₂OCH₃, CH₂OH, OC(CH₃)₃, or CH₂CH₂OCH₃.

In another embodiment, the invention features a compound of formulaI-F-4 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂,CN, CF₃, or OCF₃. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or—SO₂—, and R^(W) is H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, or OCF₃. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO—, or —SO₂—, and R^(W) is H, OH, NH₂, or NHR′. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H, OH, NH₂, or NHR′. In anotherembodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkyl isreplaced with —CO— and R^(W) is H. In another embodiment, W is C₁ alkylwherein one CH₂ unit of said C₁ alkyl is replaced with —CO— and R^(W) isOH. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁alkyl is replaced with —CO— and R^(W) is NH₂. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—and R^(W) is NHR′. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is H, OH, NH₂, orNHR′. In another embodiment, W is C₁ alkyl wherein one CH₂ unit of saidC₁ alkyl is replaced with —SO₂— and R^(W) is H. In another embodiment, Wis C₁ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —SO₂—and R^(W) is OH. In another embodiment, W is C₁ alkyl wherein one CH₂unit of said C₁ alkyl is replaced with —SO₂— and R^(W) is NH₂. Inanother embodiment, W is C₁ alkyl wherein one CH₂ unit of said C₁ alkylis replaced with —SO₂— and R^(W) is NHR′.

In another embodiment, the invention features a compound of formulaI-F-4 and the attendant definitions, wherein W is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) absent. In another embodiment, W isC₂ alkyl wherein one CH₂ unit of said C₂ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—, and R^(W) is absent. In another embodiment, Wis C₂ alkyl wherein one CH₂ unit of said C₁ alkyl is replaced with —CO—,or —SO₂—, and R^(W) is absent.

In another embodiment, the invention features a compound of formulaI-F-4 and the attendant definitions, wherein A₁ and A₂, together withWR^(W), are selected from:

In another embodiment, the invention features a compound of formulaI-F-4 and the attendant definitions, wherein R¹ is H. In anotherembodiment, R¹ is halogen. In another embodiment, R¹ is CN. In anotherembodiment, R¹ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R¹ is CF₃.

In another embodiment, the invention features a compound of formulaI-F-4 and the attendant definitions, wherein R² is H. In anotherembodiment, R² is halogen. In another embodiment, R² is Cl. In anotherembodiment, R² is F. In another embodiment, R² is CN. In anotherembodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R² is CF₃. In anotherembodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl is replacedwith —O—. In another embodiment, R² is OCF₃. In another embodiment, R²is F, Cl, CN, CF₃ or OCF₃.

In another embodiment, the invention features a compound of formulaI-F-4 and the attendant definitions, wherein R³ is H. In anotherembodiment, R³ is halogen. In another embodiment, R³ is Cl. In anotherembodiment, R³ is F. In another embodiment, R³ is CN. In anotherembodiment, R³ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R³ is t-butyl. In anotherembodiment, R³ is CF₃. In another embodiment, R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formulaI-F-4 and the attendant definitions, wherein R⁴ is H. In anotherembodiment, R⁴ is halogen. In another embodiment, R⁴ is CN. In anotherembodiment, R⁴ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R⁴ is CF₃.

In another embodiment, the invention features a compound of formulaI-F-4 and the attendant definitions, wherein R¹, R², R³, and R⁴ is H.

In another embodiment, the invention features a compound of formulaI-F-4 and the attendant definitions, wherein R⁵ is halogen. In anotherembodiment, R⁵ is Cl. In another embodiment, R⁵ is F. In anotherembodiment, R⁵ is CN. In another embodiment, R⁵ is —X—R^(X). In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent. In anotherembodiment, R⁵ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen. In anotherembodiment, R⁵ is CH₃. In another embodiment, R⁵ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁵ is OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, or OCH(CH₃)₂. In another embodiment, R⁵ is OCH₃. In anotherembodiment, R⁵ is CH₂OH. In another embodiment, R⁵ is OCF₃. In anotherembodiment, R⁵ is OCHF₂.

In another embodiment, the invention features a compound of formulaI-F-4 and the attendant definitions, wherein R⁷ is H. In anotherembodiment, R⁷ is halogen. In another embodiment, R⁷ is Cl. In anotherembodiment, R⁷ is F. In another embodiment, R⁷ is CN. In anotherembodiment, R⁷ is —X—R^(X). In another embodiment, R⁷ is —X—R^(X)wherein R^(X) is absent. In another embodiment, R⁷ is —X—R^(X) whereinR^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen. In another embodiment, R⁷ is CH₃, CH₂CH₃,CH₂CH₂CH₃ or isopropyl. In another embodiment, R⁷ is CF₃. In anotherembodiment, R⁷ is —X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen wherein twonon-adjacent CH₂ units of said C₁-C₆ alkyl are replaced with —O—. Inanother embodiment, R⁷ is OCH₂CH₂OCH₃. In another embodiment, R⁷ is—X—R^(X) wherein R^(X) is absent and X is C₁-C₆ alkyl wherein said C₁-C₆alkyl is substituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆alkyl is replaced with —O—. In another embodiment, R⁷ is OCH₃, OCH₂CH₃,OCH₂CH₂CH₃, OC(CH₃)₃, CH₂CH₂OCH₃. In another embodiment, R⁷ is OCF₃,OCH₂CF₃, OCH₂CH₂CH₂CF₃, or OCHF₂.

In another embodiment, the invention features a compound of formulaI-F-4 wherein R⁷ is —X—R^(X) wherein X is a bond and R^(X) is C₃-C₈cycloaliphatic and said C₃-C₈ cycloaliphatic is substituted with 0-3substituents selected from halogen and C₁-C₄ alkyl. In anotherembodiment, R⁷ is —X—R^(X) wherein X is a bond and R^(X) is cyclopropyl.

In another embodiment, the invention features a compound of formulaI-F-4 and the attendant definitions, wherein R⁷ is —X—R^(X) wherein X isC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein one CH₂ unit of said C₁-C₆ alkyl is replaced with —O— and R^(X)is C₃-C₈ cycloaliphatic and said C₃-C₈ cycloaliphatic is substitutedwith up 0-3 substituents selected from halogen and C₁-C₄ alkyl. Inanother embodiment, R⁷ is —X—R^(X) wherein X is OCH₂ and R^(X) iscyclopropyl.

In another embodiment, the invention features a compound of formulaI-F-4 and the attendant definitions, wherein ring A is selected from:

In another embodiment, the invention features a compound of formula I orI′, wherein the compound or a pharmaceutically acceptable salt thereof,is selected from Table 1. Compounds names in Table 1 were generatedusing ChemBioDrawUltra version 12.0 from Cambridge Soft/Chem Office2010.

TABLE 1 Compound Numbers, Structures and Chemical Names  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

In one embodiment, the compound is3-(4-fluoro-2-methoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)quinoxaline-2-carboxamide.

In another embodiment, the compound is3-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide.

In another embodiment, the compound is3-(2-chloro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide.

In another embodiment, the compound is3-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide.

In another embodiment, the compound is4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)picolinicacid.

In another embodiment, the compound is2-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide.

In another embodiment, the compound is2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide.

In another embodiment, the compound is3-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide.

In another embodiment, the compound isN-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)quinoline-3-carboxamide.

In another embodiment, the compound isN-(3-sulfamoylphenyl)-3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide.

In another embodiment, the compound is3-(4-chloro-2-methylphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide.

In another embodiment, the compound is5-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)picolinicacid.

In another embodiment, the compound is3-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)quinoxaline-2-carboxamide.

In another embodiment, the compound is3-(4-fluoro-2-methoxyphenoxy)-N-(pyridin-4-yl)quinoxaline-2-carboxamide.

In another embodiment, the compound is3-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide.

In another embodiment, the compound isN-(3-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide.

In another embodiment, the compound isN-(4-carbamoylphenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide.

In another embodiment, the compound is4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)benzoicacid.

In another embodiment, the compound isN-(4-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide.

Salts, Compositions, Uses, Formulation, Administration and AdditionalAgents

Pharmaceutically Acceptable Salts and Compositions

As discussed herein, the invention provides compounds that areinhibitors of voltage-gated sodium channels, and thus the presentcompounds are useful for the treatment of diseases, disorders, andconditions including, but not limited to chronic pain, gut pain,neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain,cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Toothsyndrome, incontinence or cardiac arrhythmia. Accordingly, in anotheraspect of the invention, pharmaceutically acceptable compositions areprovided, wherein these compositions comprise any of the compounds asdescribed herein, and optionally comprise a pharmaceutically acceptablecarrier, adjuvant or vehicle. In certain embodiments, these compositionsoptionally further comprise one or more additional therapeutic agents.

It will also be appreciated that certain of the compounds of inventioncan exist in free form for treatment, or where appropriate, as apharmaceutically acceptable derivative thereof. According to theinvention, a pharmaceutically acceptable derivative includes, but is notlimited to, pharmaceutically acceptable salts, esters, salts of suchesters, or any other adduct or derivative which upon administration to asubject in need is capable of providing, directly or indirectly, acompound as otherwise described herein, or a metabolite or residuethereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” means any non-toxic salt or salt ofan ester of a compound of this invention that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. As used herein, the term “inhibitorily activemetabolite or residue thereof” means that a metabolite or residuethereof is also an inhibitor of a voltage-gated sodium channel.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge, et al. describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄ alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersable products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

As described herein, the pharmaceutically acceptable compositions of theinvention additionally comprise a pharmaceutically acceptable carrier,adjuvant, or vehicle, which, as used herein, includes any and allsolvents, diluents, or other liquid vehicle, dispersion or suspensionaids, surface active agents, isotonic agents, thickening or emulsifyingagents, preservatives, solid binders, lubricants and the like, as suitedto the particular dosage form desired. Remington's PharmaceuticalSciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton,Pa., 1980) discloses various carriers used in formulatingpharmaceutically acceptable compositions and known techniques for thepreparation thereof. Except insofar as any conventional carrier mediumis incompatible with the compounds of the invention, such as byproducing any undesirable biological effect or otherwise interacting ina deleterious manner with any other component(s) of the pharmaceuticallyacceptable composition, its use is contemplated to be within the scopeof this invention. Some examples of materials which can serve aspharmaceutically acceptable carriers include, but are not limited to,ion exchangers, alumina, aluminum stearate, lecithin, serum proteins,such as human serum albumin, buffer substances such as phosphates,glycine, sorbic acid, or potassium sorbate, partial glyceride mixturesof saturated vegetable fatty acids, water, salts or electrolytes, suchas protamine sulfate, disodium hydrogen phosphate, potassium hydrogenphosphate, sodium chloride, zinc salts, colloidal silica, magnesiumtrisilicate, polyvinyl pyrrolidone, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, wool fat, sugars such aslactose, glucose and sucrose; starches such as corn starch and potatostarch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;malt; gelatin; talc; excipients such as cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil; safflower oil; sesameoil; olive oil; corn oil and soybean oil; glycols; such a propyleneglycol or polyethylene glycol; esters such as ethyl oleate and ethyllaurate; agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

In another aspect, the invention features a pharmaceutical compositioncomprising the compound of the invention and a pharmaceuticallyacceptable carrier.

In another aspect, the invention features a pharmaceutical compositioncomprising a therapeutically effective amount of the compound or apharmaceutically acceptable salt thereof of the compounds of formula Iand one or more pharmaceutically acceptable carriers or vehicles.

Uses of Compounds and Pharmaceutically Acceptable Salts and Compositions

In another aspect, the invention features a method of inhibiting avoltage-gated sodium channel in a subject comprising administering tothe subject a compound of formula I or a pharmaceutically acceptablesalt thereof or a pharmaceutical composition thereof. In another aspect,the voltage-gated sodium channel is Nav1.8.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of chronic pain, gut pain,neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain,cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Toothsyndrome, incontinence or cardiac arrhythmia comprising administering aneffective amount of a compound, a pharmaceutically acceptable saltthereof or a pharmaceutical composition of the compounds of formula I.

In another aspect, the invention features a method of treating orlessening the severity in a subject of chronic pain, gut pain,neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain,cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Toothsyndrome, incontinence or cardiac arrhythmia comprising administering aneffective amount of a compound or a pharmaceutically acceptable saltthereof or a pharmaceutical composition of the compounds of formula I.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of gut pain wherein gut paincomprises inflammatory bowel disease pain, Crohn's disease pain orinterstitial cystitis pain.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of neuropathic pain whereinneuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia,painful HIV-associated sensory neuropathy, trigeminal neuralgia, burningmouth syndrome, post-amputation pain, phantom pain, painful neuroma;traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinalstenosis, carpal tunnel syndrome, radicular pain, sciatica pain; nerveavulsion injury, brachial plexus avulsion injury; complex regional painsyndrome, drug therapy induced neuralgia, cancer chemotherapy inducedneuralgia, anti-retroviral therapy induced neuralgia; post spinal cordinjury pain, idiopathic small-fiber neuropathy, idiopathic sensoryneuropathy or trigeminal autonomic cephalalgia.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of musculoskeletal pain whereinmusculoskeletal pain comprises osteoarthritis pain, back pain, coldpain, burn pain or dental pain.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of idiopathic pain whereinidiopathic pain comprises fibromyalgia pain.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of chronic pain, gut pain,neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain,cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Toothsyndrome, incontinence or cardiac arrhythmia comprising administering aneffective amount of a compound or a pharmaceutically acceptable saltthereof or a pharmaceutical composition of the compounds of formula Iwith one or more additional therapeutic agents administered concurrentlywith, prior to, or subsequent to treatment with the compound orpharmaceutical composition.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of gut pain, wherein gut paincomprises inflammatory bowel disease pain, Crohn's disease pain orinterstitial cystitis pain wherein said method comprises administeringan effective amount of a compound, a pharmaceutically acceptable saltthereof or a pharmaceutical composition of the compounds of formula I.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of neuropathic pain, whereinneuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia,painful HIV-associated sensory neuropathy, trigeminal neuralgia, burningmouth syndrome, post-amputation pain, phantom pain, painful neuroma,traumatic neuroma, Morton's neuroma; nerve entrapment injury, spinalstenosis, carpal tunnel syndrome, radicular pain, sciatica pain; nerveavulsion injury, brachial plexus avulsion injury; complex regional painsyndrome, drug therapy induced neuralgia, cancer chemotherapy inducedneuralgia, anti-retroviral therapy induced neuralgia; post spinal cordinjury pain, idiopathic small-fiber neuropathy, idiopathic sensoryneuropathy or trigeminal autonomic cephalalgia wherein said methodcomprises administering an effective amount of a compound, apharmaceutically acceptable salt thereof or a pharmaceutical compositionof the compounds of formula I.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of musculoskeletal pain, whereinmusculoskeletal pain comprises osteoarthritis pain, back pain, coldpain, burn pain or dental pain wherein said method comprisesadministering an effective amount of a compound, a pharmaceuticallyacceptable salt thereof or a pharmaceutical composition of the compoundsof formula I.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of inflammatory pain, whereininflammatory pain comprises rheumatoid arthritis pain or vulvodyniawherein said method comprises administering an effective amount of acompound, a pharmaceutically acceptable salt thereof or a pharmaceuticalcomposition of the compounds of formula I.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of idiopathic pain, whereinidiopathic pain comprises fibromyalgia pain wherein said methodcomprises administering an effective amount of a compound, apharmaceutically acceptable salt thereof or a pharmaceutical compositionof the compounds of formula I.

In yet another aspect, the invention features a method wherein thesubject is treated with one or more additional therapeutic agentsadministered concurrently with, prior to, or subsequent to treatmentwith an effective amount of a compound, a pharmaceutically acceptablesalt thereof or a pharmaceutical composition of the compounds of formulaI.

In another aspect, the invention features a method of inhibiting avoltage-gated sodium channel in a subject comprising administering tothe subject an effective amount of a compound, a pharmaceuticallyacceptable salt thereof or a pharmaceutical composition of the compoundsof formula I. In another aspect, the voltage-gated sodium channel isNav1.8.

In another aspect, the invention features a method of inhibiting avoltage-gated sodium channel in a biological sample comprisingcontacting the biological sample with an effective amount of a compound,a pharmaceutically acceptable salt thereof or a pharmaceuticalcomposition of the compounds of formula I. In another aspect, thevoltage-gated sodium channel is Nav1.8.

In another aspect, the invention features a method of treating orlessening the severity in a subject of acute pain, chronic pain,neuropathic pain, inflammatory pain, arthritis, migraine, clusterheadaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias,epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatricdisorders, anxiety, depression, dipolar disorder, myotonia, arrhythmia,movement disorders, neuroendocrine disorders, ataxia, multiplesclerosis, irritable bowel syndrome, incontinence, visceral pain,osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy,radicular pain, sciatica, back pain, head pain, neck pain, severe pain,intractable pain, nociceptive pain, breakthrough pain, postsurgicalpain, cancer pain, stroke, cerebral ischemia, traumatic brain injury,amyotrophic lateral sclerosis, stress induced angina, exercise inducedangina, palpitations, hypertension, or abnormal gastro-intestinalmotility, comprising administering an effective amount of a compound, apharmaceutically acceptable salt thereof or a pharmaceutical compositionof the compounds of formula I.

In another aspect, the invention features a method of treating orlessening the severity in a subject of femur cancer pain; non-malignantchronic bone pain; rheumatoid arthritis; osteoarthritis; spinalstenosis; neuropathic low back pain; myofascial pain syndrome;fibromyalgia; temporomandibular joint pain; chronic visceral pain,abdominal pain; pancreatic pain; IBS pain; chronic and acute headachepain; migraine; tension headache, cluster headaches; chronic and acuteneuropathic pain, post-herpetic neuralgia; diabetic neuropathy;HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie Toothneuropathy; hereditary sensory neuropathies; peripheral nerve injury;painful neuromas; ectopic proximal and distal discharges; radiculopathy;chemotherapy induced neuropathic pain; radiotherapy-induced neuropathicpain; post-mastectomy pain; central pain; spinal cord injury pain;post-stroke pain; thalamic pain; complex regional pain syndrome; phantompain; intractable pain; acute pain, acute post-operative pain; acutemusculoskeletal pain; joint pain; mechanical low back pain; neck pain;tendonitis; injury/exercise pain; acute visceral pain; pyelonephritis;appendicitis; cholecystitis; intestinal obstruction; hernias; chestpain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain,labor pain; cesarean section pain; acute inflammatory, burn and traumapain; acute intermittent pain, endometriosis; acute herpes zoster pain;sickle cell anemia; acute pancreatitis; breakthrough pain; orofacialpain including sinusitis pain, dental pain; multiple sclerosis (MS)pain; pain in depression; leprosy pain; Behcet's disease pain; adiposisdolorosa; phlebitic pain; Guillain-Barre pain; painful legs and movingtoes; Haglund syndrome; erythromelalgia pain; Fabry's disease pain;bladder and urogenital disease, including, urinary incontinence;hyperactivity bladder; painful bladder syndrome; interstitial cystitis(IC); prostatitis; complex regional pain syndrome (CRPS), type I andtype II; widespread pain, paroxysmal extreme pain, pruritis, tinnitis,or angina-induced pain, comprising administering an effective amount ofa compound, a pharmaceutically acceptable salt thereof or apharmaceutical composition of the compounds of formula I.

In another aspect, the invention features a method of treating orlessening the severity in a subject of neuropathic pain comprisingadministering an effective amount of a compound, a pharmaceuticallyacceptable salt thereof or a pharmaceutical composition of the compoundsof formula I. In one aspect, the neuropathic pain is selected frompost-herpetic neuralgia, diabetic neuralgia, painful HIV-associatedsensory neuropathy, trigeminal neuralgia, burning mouth syndrome,post-amputation pain, phantom pain, painful neuroma, traumatic neuroma,Morton's neuroma, nerve entrapment injury, spinal stenosis, carpaltunnel syndrome, radicular pain, sciatica pain, nerve avulsion injury,brachial plexus avulsion, complex regional pain syndrome, drug therapyinduced neuralgia, cancer chemotherapy induced neuralgia,anti-retroviral therapy induced neuralgia, post spinal cord injury pain,idiopathic small-fiber neuropathy, idiopathic sensory neuropathy ortrigeminal autonomic cephalalgia.

Manufacture of Medicaments

In one aspect, the invention provides the use of a compound orpharmaceutical composition described herein for the manufacture of amedicament for use in inhibiting a voltage-gated sodium channel. Inanother aspect, the voltage-gated sodium channel is Nav1.8.

In yet another aspect, the invention provides the use of a compound orpharmaceutical composition described herein for the manufacture of amedicament for use in treating or lessening the severity in a subject ofchronic pain, gut pain, neuropathic pain, musculoskeletal pain, acutepain, inflammatory pain, cancer pain, idiopathic pain, multiplesclerosis, Charcot-Marie-Tooth syndrome, incontinence or cardiacarrhythmia.

In yet another aspect, the invention provides the use of a compound orpharmaceutical composition described herein for the manufacture of amedicament for use in treating or lessening the severity in a subject ofgut pain, wherein gut pain comprises inflammatory bowel disease pain,Crohn's disease pain or interstitial cystitis pain.

In yet another aspect, the invention provides the use of a compound orpharmaceutical composition described herein for the manufacture of amedicament for use in a treating or lessening the severity in a subjectof neuropathic pain, wherein neuropathic pain comprises post-herpeticneuralgia, diabetic neuralgia, painful HIV-associated sensoryneuropathy, trigeminal neuralgia, burning mouth syndrome,post-amputation pain, phantom pain, painful neuroma, traumatic neuroma,Morton's neuroma; nerve entrapment injury, spinal stenosis, carpaltunnel syndrome, radicular pain, sciatica pain; nerve avulsion injury,brachial plexus avulsion injury; complex regional pain syndrome, drugtherapy induced neuralgia, cancer chemotherapy induced neuralgia,anti-retroviral therapy induced neuralgia; post spinal cord injury pain,idiopathic small-fiber neuropathy, idiopathic sensory neuropathy ortrigeminal autonomic cephalalgia.

In yet another aspect, the invention provides the use of a compound orpharmaceutical composition described herein for the manufacture of amedicament for use in treating or lessening the severity in a subject ofmusculoskeletal pain, wherein musculoskeletal pain comprisesosteoarthritis pain, back pain, cold pain, burn pain or dental pain.

In yet another aspect, the invention the invention provides the use of acompound or pharmaceutical composition described herein for themanufacture of a medicament for use in treating or lessening theseverity in a subject of inflammatory pain, wherein inflammatory paincomprises rheumatoid arthritis pain or vulvodynia.

In yet another aspect, the invention provides the use of a compound orpharmaceutical composition described herein for the manufacture of amedicament for use in treating or lessening the severity in a subject ofidiopathic pain, wherein idiopathic pain comprises fibromyalgia pain.

In yet another aspect, the invention provides the use of a compound orpharmaceutical composition described herein for the manufacture of amedicament in combination with one or more additional therapeutic agentsadministered concurrently with, prior to, or subsequent to treatmentwith the compound or pharmaceutical composition.

In another aspect, the invention provides the use of a compound orpharmaceutical composition described herein for the manufacture of amedicament for use in treating or lessening the severity of acute pain,chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine,cluster headaches, trigeminal neuralgia, herpetic neuralgia, generalneuralgias, epilepsy, epilepsy conditions, neurodegenerative disorders,psychiatric disorders, anxiety, depression, dipolar disorder, myotonia,arrhythmia, movement disorders, neuroendocrine disorders, ataxia,multiple sclerosis, irritable bowel syndrome, incontinence, visceralpain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy,radicular pain, sciatica, back pain, head pain, neck pain, severe pain,intractable pain, nociceptive pain, breakthrough pain, postsurgicalpain, cancer pain, stroke, cerebral ischemia, traumatic brain injury,amyotrophic lateral sclerosis, stress induced angina, exercise inducedangina, palpitations, hypertension, or abnormal gastro-intestinalmotility.

In another aspect, the invention provides the use of a compound orpharmaceutical composition described herein for the manufacture of amedicament for use in treating or lessening the severity of femur cancerpain; non-malignant chronic bone pain; rheumatoid arthritis;osteoarthritis; spinal stenosis; neuropathic low back pain; myofascialpain syndrome; fibromyalgia; temporomandibular joint pain; chronicvisceral pain, abdominal pain; pancreatic pain; IBS pain; chronic andacute headache pain; migraine; tension headache, including, clusterheadaches; chronic and acute neuropathic pain, post-herpetic neuralgia;diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia;Charcot-Marie Tooth neuropathy; hereditary sensory neuropathies;peripheral nerve injury; painful neuromas; ectopic proximal and distaldischarges; radiculopathy; chemotherapy induced neuropathic pain;radiotherapy-induced neuropathic pain; post-mastectomy pain; centralpain; spinal cord injury pain; post-stroke pain; thalamic pain; complexregional pain syndrome; phantom pain; intractable pain; acute pain,acute post-operative pain; acute musculoskeletal pain; joint pain;mechanical low back pain; neck pain; tendonitis; injury/exercise pain;acute visceral pain; pyelonephritis; appendicitis; cholecystitis;intestinal obstruction; hernias; chest pain, cardiac pain; pelvic pain,renal colic pain, acute obstetric pain, labor pain; cesarean sectionpain; acute inflammatory, burn and trauma pain; acute intermittent pain,endometriosis; acute herpes zoster pain; sickle cell anemia; acutepancreatitis; breakthrough pain; orofacial pain including sinusitispain, dental pain; multiple sclerosis (MS) pain; pain in depression;leprosy pain; Behcet's disease pain; adiposis dolorosa; phlebitic pain;Guillain-Barre pain; painful legs and moving toes; Haglund syndrome;erythromelalgia pain; Fabry's disease pain; bladder and urogenitaldisease, including, urinary incontinence; hyperactivity bladder; painfulbladder syndrome; interstitial cyctitis (IC); prostatitis; complexregional pain syndrome (CRPS), type I and type II; widespread pain,paroxysmal extreme pain, pruritis, tinnitis, or angina-induced pain.

In another aspect, the invention provides the use of a compound orpharmaceutical composition described herein for the manufacture of amedicament for use in treating or lessening the severity of neuropathicpain. In one aspect, the neuropathic pain is selected from post-herpeticneuralgia, diabetic neuralgia, painful HIV-associated sensoryneuropathy, trigeminal neuralgia, burning mouth syndrome,post-amputation pain, phantom pain, painful neuroma, traumatic neuroma,Morton's neuroma, nerve entrapment injury, spinal stenosis, carpaltunnel syndrome, radicular pain, sciatica pain, nerve avulsion injury,brachial plexus avulsion, complex regional pain syndrome, drug therapyinduced neuralgia, cancer chemotherapy induced neuralgia,anti-retroviral therapy induced neuralgia, post spinal cord injury pain,idiopathic small-fiber neuropathy, idiopathic sensory neuropathy ortrigeminal autonomic cephalalgia.

Administration of Pharmaceutically Acceptable Salts and Compositions

In certain embodiments of the invention an “effective amount” of thecompound, a pharmaceutically acceptable salt thereof or pharmaceuticallyacceptable composition is that amount effective for treating orlessening the severity of one or more of chronic pain, gut pain,neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain,cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Toothsyndrome, incontinence or cardiac arrhythmia.

The compounds and compositions, according to the method of theinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of oneor more of the pain or non-pain diseases recited herein. The exactamount required will vary from subject to subject, depending on thespecies, age, and general condition of the subject, the severity of theinfection, the particular agent, its mode of administration, and thelike. The compounds of the invention are preferably formulated in dosageunit form for ease of administration and uniformity of dosage. Theexpression “dosage unit form” as used herein refers to a physicallydiscrete unit of agent appropriate for the subject to be treated. Itwill be understood, however, that the total daily usage of the compoundsand compositions of the invention will be decided by the attendingphysician within the scope of sound medical judgment. The specificeffective dose level for any particular subject or organism will dependupon a variety of factors including the disorder being treated and theseverity of the disorder; the activity of the specific compoundemployed; the specific composition employed; the age, body weight,general health, sex and diet of the subject; the time of administration,route of administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific compound employed, and like factors wellknown in the medical arts. The term “subject” or “patient,” as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the invention, it isoften desirable to slow the absorption of the compound from subcutaneousor intramuscular injection. This may be accomplished by the use of aliquid suspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the compound then depends upon itsrate of dissolution that, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered compound form is accomplished by dissolving or suspendingthe compound in an oil vehicle. Injectable depot forms are made byforming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar—agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the inventioncontemplates the use of transdermal patches, which have the addedadvantage of providing controlled delivery of a compound to the body.Such dosage forms are prepared by dissolving or dispensing the compoundin the proper medium. Absorption enhancers can also be used to increasethe flux of the compound across the skin. The rate can be controlled byeither providing a rate controlling membrane or by dispersing thecompound in a polymer matrix or gel.

As described generally above, the compounds of the invention are usefulas inhibitors of voltage-gated sodium channels. In one embodiment, thecompounds and compositions of the invention are inhibitors of Na_(V)1.8and thus, without wishing to be bound by any particular theory, thecompounds and compositions are particularly useful for treating orlessening the severity of a disease, condition, or disorder whereactivation or hyperactivity of Na_(V)1.8 is implicated in the disease,condition, or disorder. When activation or hyperactivity of Na_(V)1.8 isimplicated in a particular disease, condition, or disorder, the disease,condition, or disorder may also be referred to as a “Na_(V)1.8-mediateddisease, condition or disorder.” Accordingly, in another aspect, theinvention provides a method for treating or lessening the severity of adisease, condition, or disorder where activation or hyperactivity ofNa_(V)1.8 is implicated in the disease state.

The activity of a compound utilized in this invention as an inhibitor ofNa_(V)1.8 may be assayed according to methods described generally in theExamples herein, or according to methods available to one of ordinaryskill in the art.

Additional Therapeutic Agents

It will also be appreciated that the compounds and pharmaceuticallyacceptable compositions of the invention can be employed in combinationtherapies, that is, the compounds and pharmaceutically acceptablecompositions can be administered concurrently with, prior to, orsubsequent to, one or more other desired therapeutics or medicalprocedures. The particular combination of therapies (therapeutics orprocedures) to employ in a combination regimen will take into accountcompatibility of the desired therapeutics and/or procedures and thedesired therapeutic effect to be achieved. It will also be appreciatedthat the therapies employed may achieve a desired effect for the samedisorder (for example, an inventive compound may be administeredconcurrently with another agent used to treat the same disorder), orthey may achieve different effects (e.g., control of any adverseeffects). As used herein, additional therapeutic agents that arenormally administered to treat or prevent a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated.” For example, exemplary additional therapeutic agentsinclude, but are not limited to: nonopioid analgesics (indoles such asEtodolac, Indomethacin, Sulindac, Tolmetin; naphthylalkanones such saNabumetone; oxicams such as Piroxicam; para-aminophenol derivatives,such as Acetaminophen; propionic acids such as Fenoprofen, Flurbiprofen,Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylatessuch as Aspirin, Choline magnesium trisalicylate, Diflunisal; fenamatessuch as meclofenamic acid, Mefenamic acid; and pyrazoles such asPhenylbutazone); or opioid (narcotic) agonists (such as Codeine,Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine,Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine, Butorphanol,Dezocine, Nalbuphine, and Pentazocine). Additionally, nondrug analgesicapproaches may be utilized in conjunction with administration of one ormore compounds of the invention. For example, anesthesiologic(intraspinal infusion, neural blockade), neurosurgical (neurolysis ofCNS pathways), neurostimulatory (transcutaneous electrical nervestimulation, dorsal column stimulation), physiatric (physical therapy,orthotic devices, diathermy), or psychologic (cognitivemethods-hypnosis, biofeedback, or behavioral methods) approaches mayalso be utilized. Additional appropriate therapeutic agents orapproaches are described generally in The Merck Manual, NineteenthEdition, Ed. Robert S. Porter and Justin L. Kaplan, Merck Sharp &DohmeCorp., a subsidiary of Merck & Co., Inc., 2011, and the Food and DrugAdministration website, www.fda.gov, the entire contents of which arehereby incorporated by reference.

In another embodiment, additional appropriate therapeutic agents areselected from the following:

(1) an opioid analgesic, e.g. morphine, heroin, hydromorphone,oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl,cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene,nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol,nalbuphine or pentazocine;

(2) a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin,diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal,flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac,meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen,nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone,piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac;

(3) a barbiturate sedative, e.g. amobarbital, aprobarbital,butabarbital, butalbital, mephobarbital, metharbital, methohexital,pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal orthiopental;

(4) a benzodiazepine having a sedative action, e.g. chlordiazepoxide,clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam ortriazolam;

(5) a histamine (H₁) antagonist having a sedative action, e.g.diphenhydramine, pyrilamine, promethazine, chlorpheniramine orchlorcyclizine;

(6) a sedative such as glutethimide, meprobamate, methaqualone ordichloralphenazone;

(7) a skeletal muscle relaxant, e.g. baclofen, carisoprodol,chlorzoxazone, cyclobenzaprine, methocarbamol or orphenadrine;

(8) an NMDA receptor antagonist, e.g. dextromethorphan((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinolinequinine, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine,EN-3231 (MorphiDex®), a combination formulation of morphine anddextromethorphan), topiramate, neramexane or perzinfotel including anNR2B antagonist, e.g. ifenprodil, traxoprodil or(−)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl-3,4-dihydro-2(1H)-quinolinone;

(9) an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine,guanfacine, dexmedetomidine, modafinil, or4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1,2,3,4-tetrahydroisoquinolin-2-yl)-5-(2-pyridyl)quinazoline;

(10) a tricyclic antidepressant, e.g. desipramine, imipramine,amitriptyline or nortriptyline;

(11) an anticonvulsant, e.g. carbamazepine (Tegretol®), lamotrigine,topiramate, lacosamide (Vimpat®) or valproate;

(12) a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1antagonist, e.g.(alphaR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione(TAK-637),5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one(MK-869), aprepitant, lanepitant, dapitant or3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine(2S,3S);

(13) a muscarinic antagonist, e.g oxybutynin, tolterodine, propiverine,tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;

(14) a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib, parecoxib,valdecoxib, deracoxib, etoricoxib, or lumiracoxib;

(15) a coal-tar analgesic, in particular paracetamol;

(16) a neuroleptic such as droperidol, chlorpromazine, haloperidol,perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine,clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole,aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone,raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride,balaperidone, palindore, eplivanserin, osanetant, rimonabant,meclinertant, Miraxion® or sarizotan;

(17) a vanilloid receptor agonist (e.g. resinferatoxin or civamide) orantagonist (e.g. capsazepine, GRC-15300);

(18) a beta-adrenergic such as propranolol;

(19) a local anaesthetic such as mexiletine;

(20) a corticosteroid such as dexamethasone;

(21) a 5-HT receptor agonist or antagonist, particularly a 5-HT_(1B/1D)agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan orrizatriptan;

(22) a 5-HT_(2A) receptor antagonist such asR(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol(MDL-100907);

(23) a cholinergic (nicotinic) analgesic, such as ispronicline(TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403),(R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine;

(24) Tramadol, Tramadol ER (Ultram ER®), Tapentadol ER (Nucynta®);

(25) a PDE5 inhibitor, such as5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one(sildenafil),(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]-pyrido[3,4-b]indole-1,4-dione(IC-351 or tadalafil),2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one(vardenafil),5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide,3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide;

(26) an alpha-2-delta ligand such as gabapentin (Neurontin®), gabapentinGR (Gralise®), gabapentin, enacarbil (Horizant®), pregabalin (Lyrica®),3-methyl gabapentin,(1[alpha],3[alpha],5[alpha])(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-aceticacid, (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid,(3S,5R)-3-amino-5-methyl-heptanoic acid,(3S,5R)-3-amino-5-methyl-octanoic acid,(2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)-proline,[(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid,3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one,C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine,(3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid,(3S,5R)-3-aminomethyl-5-methyl-octanoic acid,(3S,5R)-3-amino-5-methyl-nonanoic acid,(3S,5R)-3-amino-5-methyl-octanoic acid,(3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and(3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid;

(27) a cannabinoid such as KHK-6188;

(28) metabotropic glutamate subtype 1 receptor (mGluR1) antagonist;

(29) a serotonin reuptake inhibitor such as sertraline, sertralinemetabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetinedesmethyl metabolite), fluvoxamine, paroxetine, citalopram, citaloprammetabolite desmethylcitalopram, escitalopram, d,1-fenfluramine,femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine,nefazodone, cericlamine and trazodone;

(30) a noradrenaline (norepinephrine) reuptake inhibitor, such asmaprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine,tomoxetine, mianserin, bupropion, bupropion metabolite hydroxybupropion,nomifensine and viloxazine (Vivalan®), especially a selectivenoradrenaline reuptake inhibitor such as reboxetine, in particular(S,S)-reboxetine;

(31) a dual serotonin-noradrenaline reuptake inhibitor, such asvenlafaxine, venlafaxine metabolite 0-desmethylvenlafaxine,clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine(Cymbalta®), milnacipran and imipramine;

(32) an inducible nitric oxide synthase (iNOS) inhibitor such asS-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine,5-[2-[(1-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine,S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine,(2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid,2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butyl]thio]-S-chloro-S-pyridinecarbonitrile;2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile,(2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol,2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile,2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile,N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine,NXN-462, or guanidinoethyldisulfide;

(33) an acetylcholinesterase inhibitor such as donepezil;

(34) a prostaglandin E2 subtype 4 (EP4) antagonist such asN-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide or4-[(15)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoicacid;

(35) a leukotriene B4 antagonist; such as1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylicacid (CP-105696),5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valericacid (ONO-4057) or DPC-11870;

(36) a 5-lipoxygenase inhibitor, such as zileuton,6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone(ZD-2138), or 2,3,5-trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone(CV-6504);

(37) a sodium channel blocker, such as lidocaine, lidocaine plustetracaine cream (ZRS-201) or eslicarbazepine acetate;

(38) an Na_(V)1.7 blocker, such as XEN-402 and such as those disclosedin WO2011/140425; WO2012/106499; WO2012/112743; WO2012/125613 orPCT/US2013/21535 the entire contents of each application herebyincorporated by reference.

(39) an Na_(V)1.8 blocker, such as those disclosed in WO2008/135826 andWO2006/011050 the entire contents of each application herebyincorporated by reference.

(40) a combined Na_(V)1.7 and Na_(V)1.8 blocker, such as DSP-2230 orBL-1021;

(41) a 5-HT3 antagonist, such as ondansetron;

(42) a TPRV 1 receptor agonist, such as capsaicin (NeurogesX®,Qutenza®); and the pharmaceutically acceptable salts and solvatesthereof;

(43) a nicotinic receptor antagonist, such as varenicline;

(44) an N-type calcium channel antagonist, such as Z-160;

(45) a nerve growth factor antagonist, such as tanezumab;

(46)_an endopeptidase stimulant, such as senrebotase;

(47) an angiotensin II antagonist, such as EMA-401;

In one embodiment, the additional appropriate therapeutic agents areselected from V-116517, Pregabalin, controlled release Pregabalin,Ezogabine (Potiga®). Ketamine/amitriptyline topical cream (Amiket®),AVP-923, Perampanel (E-2007), Ralfinamide, transdermal bupivacaine(Eladur®), CNV1014802, JNJ-10234094 (Carisbamate), BMS-954561 orARC-4558.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. The amount of additional therapeutic agent in thepresently disclosed compositions will range from about 10% to 100% ofthe amount normally present in a composition comprising that agent asthe only therapeutically active agent.

The compounds of this invention or pharmaceutically acceptablecompositions thereof may also be incorporated into compositions forcoating an implantable medical device, such as prostheses, artificialvalves, vascular grafts, stents and catheters. Accordingly, theinvention, in another aspect, includes a composition for coating animplantable device comprising a compound of the invention as describedgenerally above, and in classes and subclasses herein, and a carriersuitable for coating said implantable device. In still another aspect,the invention includes an implantable device coated with a compositioncomprising a compound of the invention as described generally above, andin classes and subclasses herein, and a carrier suitable for coatingsaid implantable device. Suitable coatings and the general preparationof coated implantable devices are described in U.S. Pat. Nos. 6,099,562;5,886,026; and 5,304,121. The coatings are typically biocompatiblepolymeric materials such as a hydrogel polymer, polymethyldisiloxane,polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinylacetate, and mixtures thereof. The coatings may optionally be furthercovered by a suitable topcoat of fluorosilicone, polysaccarides,polyethylene glycol, phospholipids or combinations thereof to impartcontrolled release characteristics in the composition.

Another aspect of the invention relates to inhibiting Na_(V)1.8 activityin a biological sample or a subject, which method comprisesadministering to the subject, or contacting said biological sample witha compound of formula I or a composition comprising said compound. Theterm “biological sample,” as used herein, includes, without limitation,cell cultures or extracts thereof; biopsied material obtained from amammal or extracts thereof; and blood, saliva, urine, feces, semen,tears, or other body fluids or extracts thereof.

Inhibition of Na_(V)1.8 activity in a biological sample is useful for avariety of purposes that are known to one of skill in the art. Examplesof such purposes include, but are not limited to, the study of sodiumchannels in biological and pathological phenomena; and the comparativeevaluation of new sodium channel inhibitors.

SCHEMES AND EXAMPLES

The compounds of the invention may be prepared readily using thefollowing methods. Illustrated below in Scheme 1 is a general method forpreparing the compounds of the present invention.

Scheme 1: General Preparation of Compounds of Formula I

EXAMPLES

General methods. ¹H NMR (400 MHz) spectra were obtained as solutions inan appropriate deuterated solvent such as dimethyl sulfoxide-d₆ (DMSO).Mass spectra (MS) were obtained using an Applied Biosystems API EX LC/MSsystem. Compound purity and retention times were determined by reversephase HPLC using a Kinetix C18 column (50×2.1 mm, 1.7 μm particle) fromPhenomenex (pn: 00B-4475-AN)), and a dual gradient run from 1-99% mobilephase B over 3 minutes. Mobile phase A=H₂O (0.05% CF₃CO₂H). Mobile phaseB=CH₃CN (0.05% CF₃CO₂H). Flow rate=2 mL/min, injection volume=3 μL, andcolumn temperature=50° C. Silica gel chromatography was performed usingsilica gel-60 with a particle size of 230-400 mesh. Pyridine,dichloromethane (CH₂Cl₂), tetrahydrofuran (THF), dimethylformamide(DMF), acetonitrile (ACN), methanol (MeOH), and 1,4-dioxane were fromBaker or Aldrich and in some cases the reagents were Aldrich Sure-Sealbottles kept under dry nitrogen. All reactions were stirred magneticallyunless otherwise noted.

Example 1 Preparation of5-(3-(2,4-dimethoxyphenoxy)quinoxaline-2-carboxamido)picolinic acid (26)

To 3-hydroxyquinoxaline-2-carboxylic acid (10.94 g, 57.53 mmol) wasadded thionyl chloride (109.1 mL, 1496 mmol) and DMF (35 drops) and thereaction was refluxed at 80° C. for 17 hours. The excess thionylchloride and N,N-dimethyl formamide were removed in vacuo to yield3-chloroquinoxaline-2-carbonyl chloride (13 g, 99%) as a brown solid. ¹HNMR (400 MHz, DMSO-d6) δ 8.27-8.18 (m, 1H), 8.18-8.09 (m, 1H), 8.09-7.93(m, 2H) ppm.

A solution of 3-chloroquinoxaline-2-carbonyl chloride (3.5 g, 15.45mmol) in dichloromethane (32.3 mL) was added dropwise to a mixture ofmethyl 5-aminopyridine-2-carboxylate (2.35 g, 15.45 mmol), pyridine(3.75 mL, 46.35 mmol) and dichloromethane (48.38 mL) at 0° C. Themixture was stirred and allowed to warm up to room temperatureovernight. To the reaction, water (40 mL) was added and the productprecipitated. The solid was isolated by filtration, washed with water(1×40 mL) and hexanes (2×50 mL) to yield methyl5-[(3-chloroquinoxaline-2-carbonyl)amino]pyridine-2-carboxylate (4.31 g,81%) as a cream colored solid. ¹H NMR (400 MHz, DMSO-d6) δ 11.61 (s,1H), 9.00 (d, J=2.5 Hz, 1H), 8.46 (dd, J=8.6, 2.6 Hz, 1H), 8.36-8.26 (m,1H), 8.24-8.12 (m, 2H), 8.12-7.95 (m, 2H), 3.89 (s, 3H) ppm. ESI-MS m/zcalc. 342.05, found 343.4 (M+1)+; Retention time: 1.25 minutes (3minutes run).

To methyl5-[(3-chloroquinoxaline-2-carbonyl)amino]pyridine-2-carboxylate (51.41mg, 0.15 mmol) in NMP (1 mL) was added 2,4-dimethoxyphenol (23.12 mg,0.15 mmol) and potassium carbonate (62.19 mg, 0.45 mmol) and thereaction was heated at 100° C. for 1.5 hours. To the reaction were added150 μL of MeOH and 150 μL of 3M sodium hydroxide and the reaction wasstirred at 50° C. for 1.5 hours. The reaction was cooled to 25° C.,filtered and purified by reverse phase preparative chromatographyutilizing a gradient of 10-99% acetonitrile in water containing HCl as amodifier to yield5-(3-(2,4-dimethoxyphenoxy)quinoxaline-2-carboxamido)picolinic acid (26)(26.63 mg, 36%). ¹H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 9.05 (d,J=2.5 Hz, 1H), 8.45 (dd, J=8.6, 2.5 Hz, 1H), 8.18 (dd, J=8.4, 1.6 Hz,1H), 8.14 (d, J=8.6 Hz, 1H), 7.90-7.71 (m, 3H), 7.22 (d, J=8.7 Hz, 1H),6.76 (d, J=2.8 Hz, 1H), 6.60 (dd, J=8.8, 2.8 Hz, 1H), 3.81 (s, 3H), 3.68(s, 3H). ESI-MS m/z calc. 346.12, found 347.2 (M+1)+; Retention time:1.30 minutes (3 minutes run).

The following compounds were prepared using a procedure similar as theone described above from the following alcohols.

Cmpd. No. Product name Alcohol 235-(3-(4-chloro-2-methoxyphenoxy)quinoxaline-2- 4-chloro-2-methoxy-phenolcarboxamido)picolinic acid 285-(3-(2-chloro-4-fluorophenoxy)quinoxaline-2- 2-chloro-4-fluoro-phenolcarboxamido)picolinic acid 255-(3-(4-chloro-2-methylphenoxy)quinoxaline-2- 4-chloro-2-methyl-phenolcarboxamido)picolinic acid 315-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-4-(trifluoromethoxy)phenol carboxamido)picolinic acid 305-(3-(2-chloro-4-methoxyphenoxy)quinoxaline-2- 2-chloro-4-methoxy-phenolcarboxamido)picolinic acid 195-(3-(4-fluoro-2-methylphenoxy)quinoxaline-2- 4-fluoro-2-methyl-phenolcarboxamido)picolinic acid 225-(3-(4-(2,2,2-trifluoroethoxy)phenoxy)quinoxaline-2- 2,2,2-carboxamido)picolinic acid trifluoroethoxy)phenol 295-(3-(2,4-difluorophenoxy)quinoxaline-2- 2,4-difluorophenolcarboxamido)picolinic acid 275-(3-(3-fluoro-4-methoxyphenoxy)quinoxaline-2- 3-fluoro-4-methoxy-phenolcarboxamido)picolinic acid 215-(3-(2-fluoro-4-methoxyphenoxy)quinoxaline-2- 2-fluoro-4-methoxy-phenolcarboxamido)picolinic acid 18 5-(3-(4-fluorophenoxy)quinoxaline-2-4-fluorophenol carboxamido)picolinic acid 245-(3-(2-(difluoromethoxy)phenoxy)quinoxaline-2-2-(difluoromethoxy)phenol carboxamido)picolinic acid 205-(3-phenoxyquinoxaline-2-carboxamido)picolinic acid phenol

Example 2 Preparation of5-(3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamido)picolinic acid(32)

A mixture of ethyl 3-chloroquinoxaline-2-carboxylate (300 mg, 1.27mmol), 4-fluoro-2-methoxy-phenol (289.0 μL, 2.54 mmol) and Cs₂CO₃ (826.3mg, 2.54 mmol) in NMP (3.0 mL) was stirred at 100° C. for 3 hours. Thereaction mixture was poured into water, the pH was adjusted to pH 6 with1N HCl and the mixture was extracted with ethyl acetate (3×). Theorganics were combined, washed with brine, dried over Na₂SO₄ andevaporated to dryness. Purification by column chromatography using agradient of MeOH in dichloromethane (0-10%) gave3-(4-fluoro-2-methoxy-phenoxy)quinoxaline-2-carboxylic acid (360 mg,90%) as a red oil. ESI-MS m/z calc. 314.07, found 315.1 (M+1)+;Retention time: 1.35 minutes (3 minutes run).

A solution of the 5-aminopicolinic acid methyl ester (15.2 mg, 0.1mmol), 3-(4-fluoro-2-methoxy-phenoxy)quinoxaline-2-carboxylic acid(34.57 mg, 0.11 mmol), N-methylmorpholine (21.99 μL, 0.2 mmol) and HATU(45.6 mg, 0.12 mmol) in DMF (0.4 mL) was stirred at 40° C. for 16 hours.3M aqueous NaOH solution (0.50 mmol, 166.7 μL) and methanol (0.2 mL) wasadded and the reaction mixture was stirred at 40° C. for 1 hour. Themixture was diluted with MeOH, filtered and purification by reversephase HPLC using a gradient of 1-99% ACN in water and HCl as a modifierto yield5-(3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamido)picolinic acid(32) (10.75 mg, 23%). ESI-MS m/z calc. 434.10, found 435.3 (M+1)+;Retention time: 1.33 minutes (3 minutes run). ¹H NMR (400 MHz, DMSO) δ13.12 (s br, 1H), 11.52 (s, 1H), 9.06 (d, J=2.3 Hz, 1H), 8.45 (dd,J=8.6, 2.5 Hz, 1H), 8.20 (d, J=7.8 Hz, 1H), 8.14 (d, J=8.6 Hz, 1H), 7.82(ddd, J=24.3, 15.6, 6.7 Hz, 3H), 7.36 (dd, J=8.8, 5.8 Hz, 1H), 7.16 (dd,J=10.6, 2.8 Hz, 1H), 6.88 (ddd, J=8.5, 2.8 Hz, 1H), 3.70 (s, 3H) ppm.

Example 3 Preparation of5-(2-(2-chloro-4-fluorophenoxy)quinoline-3-carboxamido)picolinic acid(79)

A solution of 2-chloroquinoline-3-carbonyl chloride (2.72 g, 12.04 mmol)in methylene chloride (37.7 mL) was added dropwise to a mixture ofmethyl 5-aminopyridine-2-carboxylate (1.83 g, 12.04 mmol), pyridine (2.9mL, 36.12 mmol) and methylene chloride (25.1 mL) at 0° C. The mixturewas stirred and allowed to warm up to room temperature over 1.5 hours.To the reaction slurry, water (30 mL) was added and a precipitateformed. The solid was filtered, washed with water (2×30 mL), hexanes(2×50 mL), and a small amount of dichloromethane. The solid from thefiltrate was isolated and washed with water (1×15 mL) and hexanes (1×20mL). This solid obtained was dried in the vacuum oven to yield methyl5-(2-chloroquinoline-3-carboxamido)picolinate (3 g, 73%). ESI-MS m/zcalc. 341.06, found 342.2 (M+1)+; Retention time: 1.18 minutes (3minutes run). ¹H NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 8.95 (d, J=2.5Hz, 1H), 8.85 (s, 1H), 8.42 (dd, J=8.6, 2.5 Hz, 1H), 8.21-8.12 (m, 2H),8.07 (dd, J=8.6, 1.1 Hz, 1H), 8.02-7.89 (m, 1H), 7.82-7.72 (m, 1H), 3.89(s, 3H) ppm.

To methyl 5-(2-chloroquinoline-3-carboxamido)picolinate (52.26 mg, 0.15mmol), 2-chloro-4-fluorophenol (21.98 mg, 0.15 mg), potassium carbonate(62.19 mg, 0.45 mmol) and 1-methylpyrrolidin-2-one (1 mL) were added andthe reactions were stirred at 100° C. for 1 hour. 2M lithium hydroxide(75 μL, 0.45 mmol) and methanol (150 μL) were added and the reactionstirred at 50° C. for 2 hours. The reaction was filtered and (75 μL,0.45 mmol) of 2M lithium hydroxide were added and stirring was continuedfor an additional 2 hours. The reaction was filtered and purified byreverse phase preparative chromatography utilizing a gradient of 10-99%acetonitrile in water containing HCl as a modifier to yield5-(2-(2-chloro-4-fluorophenoxy)quinoline-3-carboxamido)picolinic acidhydrochloric acid (79) (4.2 mg, 6%). ESI-MS m/z calc. 437.06, found338.4 (M+1)+)+; Retention time: 1.49 minutes (3 minutes run).

5-(2-(2,4-Difluorophenoxy)quinoline-3-carboxamido)picolinic acid (34)was prepared as described above from 2,4-difluorophenol.

Example 4 Preparation of4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)picolinicacid (33)

A solution of 3-chloroquinoxaline-2-carbonyl chloride (3.14 g, 13.83mmol) in dichloromethane (30.19 mL) was added dropwise to a mixture ofmethyl 4-aminopyridine-2-carboxylate (2.10 g, 13.83 mmol), pyridine(3.36 mL, 41.49 mmol) and dichloromethane (43.49 mL) at 0° C. Themixture was stirred and allowed to warm up to room temperature for 2hrs. To the reaction, water (100 mL) was added and a precipitate formed.The solid was isolated by filtration, washed with water (1×40 mL) andhexanes (2×50 mL), then with 10 ml EtOAc and 10 ml dichloromethane anddried to yield methyl4-[(3-chloroquinoxaline-2-carbonyl)amino]pyridine-2-carboxylate (2.64 g,55%) as a blue-colored solid (1.54 g). ESI-MS m/z calc. 342.05, found343.2 (M+1)+; Retention time: 0.95 minutes (3 minutes run). ¹H NMR (400MHz, DMSO-d6) δ 11.63 (s, 1H), 8.70 (d, J=5.4 Hz, 1H), 8.51 (d, J=2.1Hz, 1H), 8.34-8.27 (m, 1H), 8.24-8.16 (m, 1H), 8.13-8.00 (m, 2H), 7.94(dd, J=5.4, 2.2 Hz, 1H), 3.91 (s, 3H) ppm.

A solution of methyl4-[(3-chloroquinoxaline-2-carbonyl)amino]pyridine-2-carboxylate (2.6 g,7.59 mmol), 4-(trifluoromethoxy)phenol (982.5 μL, 7.59 mmol) and K₂CO₃(3.14 g, 22.76 mmol) in NMP (52.00 mL) was stirred at 70° C. for twohours and at room temperature for 12 hours. 120 ml of water were addedand the reaction mixture was heated to 80° C. for 60 minutes. Thereaction mixture was cooled to 45° C., aqueous HCl (1.0 N) was addeduntil a precipitate formed. This mixture was stirred for 10 minutes, andthen it was filtered. The filter cake was washed with an excess of wateruntil the pH paper showed neutral and then it was washed with an excessof hexanes. The residue was dispersed in 120 ml of ethyl acetate,stirred for 15 minutes then it was filtered. The filter cake was washedwith 10 ml ethyl acetate, 10 ml dichloromethane and dried overnight togive 44344-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)picolinicacid (33) (2.2 g, 61%) as a light tan-colored solid. ESI-MS m/z calc.470.08, found 471.3 (M+1)+; Retention time: 1.51 minutes (3 minutesrun). ¹H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 8.67 (d, J=5.5 Hz, 1H),8.51 (d, J=2.1 Hz, 1H), 8.22 (dd, J=8.4, 1.6 Hz, 1H), 7.99 (dd, J=5.5,2.2 Hz, 1H), 7.93-7.77 (m, 3H), 7.52 (s, 4H) ppm.

Using a similar experimental procedure,4-(3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamido)picolinic acid(34) was prepared.

Example 5 Preparation of4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)benzoic acid(17)

A solution of 3-chloroquinoxaline-2-carbonyl chloride (1.0 g, 4.40 mmol)in dichloromethane (9.2 mL) was added dropwise to a mixture oftert-butyl 4-aminobenzoate (851.0 mg, 4.40 mmol), pyridine (1.07 mL,13.21 mmol) and dichloromethane (13.8 mL) at 0° C. The reaction wasstirred and allowed to warm up to room temperature over 40 minutes. Tothe reaction, water (10 mL) was added. The two layers were separated.The organic layer was washed with water (2×10 mL), dried over Na₂SO₄,filtered and the solvent was evaporated under reduced pressure. Theproduct was slurried in hexanes at 40° C., and the solid was isolated byfiltration to yield tert-butyl4-[(3-chloroquinoxaline-2-carbonyl)amino]benzoate (1.34 g, 79%) as ayellow solid. ESI-MS m/z calc. 383.10, found 384.4 (M+1)+; Retentiontime: 1.88 minutes (3 minutes run). ¹H NMR (400 MHz, DMSO-d6) δ 11.28(s, 1H), 8.27 (dd, J=7.5, 2.1 Hz, 1H), 8.22-8.11 (m, 1H), 8.11-8.01 (m,2H), 7.97 (d, J=8.8 Hz, 2H), 7.86 (d, J=8.7 Hz, 2H), 1.56 (s, 9H) ppm.

To tert-butyl 4-[(3-chloroquinoxaline-2-carbonyl)amino]benzoate (102.4mg, 0.3 mmol), 4-trifluoromethylphenol (53.43 mg, 0.3 mmol), potassiumcarbonate (41.46 mg, 0.3 mmol) and N-methylpyrrolidinone (2 mL) wereadded and the reaction stirred at 100° C. for 3 hours. The reaction wasfiltered and used as is in the next step without further purification.

To tert-butyl4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)benzoateobtained in the previous step, dichloromethane (1 mL) and2,2,2-trifluoroacetic acid (5.98 g, 52.5 mmol) were added and thereaction stirred at 40° C. for 18 hours. The excess TFA anddichloromethane was evaporated under reduced pressure. The crude productwas filtered and purified by reverse phase preparative chromatographyutilizing a gradient of 30-99% acetonitrile in water containing HCl as amodifier to yield4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)benzoic acid(17) (54.6 mg, 39%). ESI-MS m/z calc. 469.09, found 470.5 (M+1)+;Retention time: 1.96 minutes (3 minutes run). ¹H NMR (400 MHz, DMSO-d6)δ 12.85 (s, 1H), 11.26 (s, 1H), 8.25-8.15 (m, 1H), 8.04-7.96 (m, 2H),7.95-7.88 (m, 2H), 7.88-7.76 (m, 3H), 7.58-7.44 (m, 4H) ppm.

Example 6 Preparation of4-(2-(2,4-difluorophenoxy)quinoline-3-carboxamido)benzoic acid (75)

To 2-chloroquinoline-3-carboxylic acid (5 g, 24.08 mmol) was addedthionyl chloride (22.83 mL, 313.0 mmol) and DMF (12 drops) and thereaction was heated at 60° C. for 16 hours. The excess thionyl chlorideand N,N-dimethyl formamide were removed in vacuo to yield2-chloroquinoline-3-carbonyl chloride as a yellow solid.

A solution of acid chloride (2.72 g, 12.04 mmol) in methylene chloride(37.7 mL) was added dropwise to a mixture of methyl 4-aminobenzoate(1.82 g, 12.04 mmol), pyridine (2.92 mL, 36.12 mmol) and methylenechloride (25.1 mL) at 0° C. The mixture was stirred and allowed to warmup to room temperature over 1.5 hours. To the reaction slurry, water (30mL) was added and the product crashed out. The solid was isolated byfiltration, washed with water (2×30 mL), hexanes (2×50 mL), and a smallamount of DCM. The product was dried in the vacuum oven to yield methyl4-(2-chloroquinoline-3-carboxamido)benzoate (3.67 g, 89%). ESI-MS m/zcalc. 340.06, found 341.2 (M+1)+; Retention time: 1.46 minutes. ¹H NMR(400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.81 (s, 1H), 8.15 (d, J=8.1 Hz,1H), 8.06 (d, J=8.4 Hz, 1H), 8.04-7.98 (m, 2H), 7.97-7.91 (m, 1H),7.91-7.85 (m, 2H), 7.80-7.74 (m, 1H), 3.85 (s, 3H) ppm.

To methyl 4-(2-chloroquinoline-3-carboxamido)benzoate (34.21 mg, 0.1mmol), 2,4-difluorophenol (13.01 mg, 0.1 mmol), potassium carbonate(13.82 mg, 0.1 mmol) and N-methyl pyrrolidinone (1 mL) were added andthe reaction was heated at 80° C. for 2.5 hours.

To the crude ester obtained in the previous step was added lithiumhydroxide (225 μL of 2M, 0.45 mmol) and methanol (150 μL) and thereaction was stirred at 50° C. for 2 hours. The reaction was filteredand 3 additional equivalents of LiOH were added and the reaction wasstirred at 50° C. for 2 hours. The reaction was cooled to 25° C.,filtered and purified by reverse phase preparative chromatographyutilizing a gradient of 10-99% acetonitrile in water containing HCl as amodifier to yield4-(2-(2,4-difluorophenoxy)quinoline-3-carboxamido)benzoic acid (75)(11.8 mg, 17%). ESI-MS m/z calc. 421.09, found 422.2 (M+1)+; Retentiontime: 1.43 minutes (3 minutes run). ¹H NMR (400 MHz, DMSO-d6) δ 11.24(s, 1H), 9.02 (d, J=2.5 Hz, 1H), 8.84 (s, 1H), 8.41 (dd, J=8.6, 2.5 Hz,1H), 8.17-8.04 (m, 2H), 7.85-7.72 (m, 1H), 7.72-7.63 (m, 1H), 7.63-7.55(m, 2H), 7.55-7.46 (m, 1H), 7.30-7.14 (m, 1H) ppm.

The following compounds were prepared using a procedure similar as theone described above from the following alcohols.

Cmpd. No. Product name Alcohol 764-(2-(4-fluoro-2-methylphenoxy)quinoline-3- 4-fluoro-2-carboxamido)benzoic acid methyl-phenol 784-(2-(2,4-dimethoxyphenoxy)quinoline-3- 2,4-dimethoxy-carboxamido)benzoic acid phenol 77 4-(2-(2- 2-(difluoro-(difluoromethoxy)phenoxy)quinoline-3- methoxy)phenol carboxamido)benzoicacid

Example 7 Preparation of3-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide(2)

A mixture of ethyl 3-chloroquinoxaline-2-carboxylate (300 mg, 1.27mmol), 4-fluoro-2-methoxy-phenol (289.0 μL, 2.54 mmol) and Cs₂CO₃ (826.3mg, 2.54 mmol) in NMP (3.0 mL) was stirred at 100° C. for 3 hours. Thereaction mixture was poured into water, the pH was adjusted to pH 6 with1N HCl and the mixture was extracted with ethyl acetate (3×). Theorganics were combined, washed with brine, dried with Na₂SO₄, filteredand evaporated to dryness. Purification by column chromatography using agradient of 0-10% MeOH in dichloromethane gave3-(4-fluoro-2-methoxy-phenoxy)quinoxaline-2-carboxylic acid (360 mg,90%) as a red oil. ESI-MS m/z calc. 314.07, found 315.1 (M+1)+;Retention time: 1.35 minutes (3 minutes run).

A solution of 3-(4-fluoro-2-methoxy-phenoxy)quinoxaline-2-carboxylicacid (47.1 mg, 0.15 mmol), 3-aminobenzenesulfonamide (31.0 mg, 0.18mmol), HATU (62.7 mg, 0.16 mmol) and N-methylmorpholine (32.98 μL, 0.30mmol) in DMF (0.5 mL) was stirred at 50° C. for 30 min. Purification wasby reverse phase HPLC using a gradient of 1-99% ACN in Water (HClmodifier). The fractions containing the product were evaporated todryness. The residue was then taken up in ethyl acetate and water andthe pH of the solution was adjusted to −8 with a saturated solution ofNaHCO₃ in water (˜3 drops). The layers separated and the aqueous layerwas extracted with ethyl acetate (3×). All organic were combined,evaporated and purification by silica gel column chromatography using agradient of ethyl acetate in hexanes (5 to 70%) gave3-(4-fluoro-2-methoxy-phenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide(2) (26.10 mg, 37%) as a white solid. ESI-MS m/z calc. 468.09, found469.3 (M+1)+; Retention time: 1.49 minutes (3 minutes run). ¹H NMR (400MHz, DMSO) δ 11.27 (s, 1H), 8.42 (s, 1H), 8.18 (d, J=8.0 Hz, 1H),7.97-7.87 (m, 1H), 7.86-7.71 (m, 3H), 7.68-7.56 (m, 2H), 7.44 (s, 2H),7.34 (dd, J=8.7, 5.9 Hz, 1H), 7.16 (dd, J=10.8, 2.9 Hz, 1H), 6.88 (ddd,J=8.6, 2.9 Hz, 1H), 3.71 (s, 3H) ppm.

The following compounds were prepared using a similar experimentalprocedure from 3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxylicacid and the following amines.

Cmpd. No. Product name Amine 46 3-(4-fluoro-2-methoxyphenoxy)-N-(3-3-(methylsulfonyl)aniline (methylsulfonyl)phenyl)quinoxaline-2-carboxamide 57 3-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-2,3- 5-amino-1H-dihydro-1H-benzo[d]imidazol-5-yl)quinoxaline-2-benzo[d]imidazol-2(3H)-one carboxamide 533-(4-fluoro-2-methoxyphenoxy)-N-(pyridin-4- 4-aminopyridineyl)quinoxaline-2-carboxamide 16 3-(4-fluoro-2-methoxyphenoxy)-N-(3-(N-3-amino-N- methylsulfamoyl)phenyl)quinoxaline-2-methylbenzenesulfonamide carboxamide 56 N-(3-cyanophenyl)-3-(4-fluoro-2-3-aminobenzonitrile methoxyphenoxy)quinoxaline-2-carboxamide 58N-(4-carbamoylphenyl)-3-(4-fluoro-2- 4-aminobenzamidemethoxyphenoxy)quinoxaline-2-carboxamide 51N-(6-cyanopyridin-3-yl)-3-(4-fluoro-2- 5-aminopicolinonitrilemethoxyphenoxy)quinoxaline-2-carboxamide 55N-(4-cyanophenyl)-3-(4-fluoro-2- 4-aminobenzonitrilemethoxyphenoxy)quinoxaline-2-carboxamide 543-(4-fluoro-2-methoxyphenoxy)-N-(pyridin-3- 3-aminopyridineyl)quinoxaline-2-carboxamide 483-(4-fluoro-2-methoxyphenoxy)-N-(1H-indazol- 1H-indazol-5-amine5-yl)quinoxaline-2-carboxamide 42N-(1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-fluoro-2-1H-benzo[d][1,2,3]triazol-5- methoxyphenoxy)quinoxaline-2-carboxamideamine 47 3-(4-fluoro-2-methoxyphenoxy)-N-(1H-indazol- 1H-indazol-6-amine6-yl)quinoxaline-2-carboxamide 59 N-(3-carbamoylphenyl)-3-(4-fluoro-2-3-aminobenzamide methoxyphenoxy)quinoxaline-2-carboxamide 433-(4-fluoro-2-methoxyphenoxy)-N-(1H-pyrazol- 1H-pyrazol-4-amine4-yl)quinoxaline-2-carboxamide 44 3-(4-fluoro-2-methoxyphenoxy)-N-(2-(5-amino-1H- (hydroxymethyl)-1H-benzo[d]imidazol-5- benzo[d]imidazol-2-yl)quinoxaline-2-carboxamide yl)methanol 49N-(1H-benzo[d]imidazol-6-yl)-3-(4-fluoro-2- 1H-benzo[d]imidazol-6-methoxyphenoxy)quinoxaline-2-carboxamide amine 383-(4-fluoro-2-methoxyphenoxy)-N-(1H-1,2,4- 1H-1,2,4-triazol-3-aminetriazol-3-yl)quinoxaline-2-carboxamide 50N-(4-cyanopyridin-2-yl)-3-(4-fluoro-2- 2-aminoisonicotinonitrilemethoxyphenoxy)quinoxaline-2-carboxamide 45N-(3-(1H-tetrazol-5-yl)phenyl)-3-(4-fluoro-2-3-(1H-tetrazol-5-yl)aniline methoxyphenoxy)quinoxaline-2-carboxamide 403-(4-fluoro-2-methoxyphenoxy)-N-(1H-pyrazol- 1H-pyrazol-3-amine3-yl)quinoxaline-2-carboxamide 413-(4-fluoro-2-methoxyphenoxy)-N-(1H-tetrazol-4-(1H-tetrazol-5-yl)aniline 5-yl)quinoxaline-2-carboxamide 52N-(5-cyanopyridin-2-yl)-3-(4-fluoro-2- 6-aminonicotinonitrilemethoxyphenoxy)quinoxaline-2-carboxamide 392-(3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-2-aminooxazole-4-carboxylic carboxamido)oxazole-4-carboxylic acid acid

Example 8 Preparation of3-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide (1)

Ethyl 3-chloroquinoxaline-2-carboxylate (473.3 mg, 2.0 mmol),4-fluorophenol (448.4 mg, 4.0 mmol) and Cs₂CO₃ (1.30 g, 4.0 mmol) in NMP(5 mL) was stirred at 80° C. for 16 hours. The reaction mixture waspoured into water and the pH adjusted to 4 with aqueous 1N HCl. Theresulting precipitate was filtered off, taken up in MeOH (3 mL). Water(0.3 mL) and NaOH (320.0 mg, 8.00 mmol) were added and the reactionmixture was stirred at 40° C. for 1 hour. The reaction mixture wasdiluted with 1N HCl. The resulting precipitate was filtered, washed withether, and dried to give 3-(4-fluorophenoxy)quinoxaline-2-carboxylicacid (120 mg, 21%) as a white solid. ESI-MS m/z calc. 284.06, found285.3 (M+1)+; Retention time: 1.29 minutes (3 minutes run).

A solution of 3-(4-fluorophenoxy)quinoxaline-2-carboxylic acid (28.42mg, 0.1 mmol), 3-aminobenzenesulfonamide (20.7 mg, 0.12 mmol), HATU(38.0 mg, 0.10 mmol) and N-methylmorpholine (21.99 μL, 0.20 mmol) in NMP(0.5 mL) and DMSO (0.1 mL) was stirred at 25° C. for 16 hours. Thereaction was filtered and purified by reverse phase HPLC using agradient of 1-99% ACN in Water and HCl as a modifier.3-(4-Fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide (1)(13.9 mg, 32%) was obtained as a white solid. ESI-MS m/z calc. 438.08,found 439.5 (M+1)+; Retention time: 1.49 minutes (3 minutes run).

Example 9 Preparation of3-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide(5)

To a solution of 3-aminobenzenesulfonamide (4.5 g, 26.43 mmol) andpyridine (12.83 mL, 158.6 mmol) in dichloromethane (48 mL) at 0° C. wasadded 3-chloroquinoxaline-2-carbonyl chloride (6.0 g, 26.43 mmol) indichloromethane (60 mL) and the mixture was stirred and allowed to warmup to room temperature overnight. To the reaction slurry, water (60 mL)was added. The solid was isolated by filtration, washed with water (3×50mL), hexane (50 mL) and a small amount of dichloromethane. The solid wasdried under vacuum to yield3-chloro-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide (7.1 g, 74%) asa salmon colored solid. ESI-MS m/z calc. 362.02, found 363.3 (M+1)+;Retention time: 1.43 minutes (3 minutes run). ¹H NMR (400 MHz, DMSO-d6)δ 11.30 (s, 1H), 8.40-8.33 (m, 1H), 8.31-8.24 (m, 1H), 8.24-8.14 (m,1H), 8.12-7.98 (m, 2H), 7.90-7.81 (m, 1H), 7.69-7.58 (m, 2H), 7.47 (s,2H) ppm.

To a solution of 3-chloro-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide(54.4 mg, 0.15 mmol) in N-methylpyrrolidinone (1 mL) was added2,4-difluorophenol (19.5 mg, 0.15 mmol) and cesium carbonate (146.6 mg,0.45 mmol) and the reaction was stirred at 100° C. for 25 minutes. Thereaction was filtered and purified by reverse phase preparativechromatography utilizing a gradient of 10-99% acetonitrile in watercontaining HCl as a modifier to yield3-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide(5) (13.2 mg, 19%). ESI-MS m/z calc. 456.07, found 457.3 (M+1)+;Retention time: 1.76 minutes (3 minutes run). ¹H NMR (400 MHz, DMSO-d6)δ 11.32 (s, 1H), 8.47-8.37 (m, 1H), 8.27-8.15 (m, 1H), 7.97-7.75 (m,4H), 7.69-7.50 (m, 4H), 7.45 (s, 2H), 7.30-7.17 (m, 1H) ppm.

The following compounds were prepared using a similar experimentalprocedure as described above for the preparation of3-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide(5) from 3-chloro-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide and thefollowing alcohols.

Cmpd. No. Product name Alcohol 6 3-(2-chloro-4-fluorophenoxy)-N-(3-2-chloro-4-fluoro-phenol sulfamoylphenyl)quinoxaline-2-carboxamide 43-(2-chloro-4-methoxyphenoxy)-N-(3- 2-chloro-4-methoxy-phenolsulfamoylphenyl)quinoxaline-2-carboxamide 113-(4-chloro-2-methoxyphenoxy)-N-(3- 4-chloro-2-methoxy-phenolsulfamoylphenyl)quinoxaline-2-carboxamide 83-(2,4-dimethoxyphenoxy)-N-(3- 2,4-dimethoxyphenolsulfamoylphenyl)quinoxaline-2-carboxamide 143-(4-fluoro-2-methylphenoxy)-N-(3- 4-fluoro-2-methyl-phenolsulfamoylphenyl)quinoxaline-2-carboxamide 3 N-(3-sulfamoylphenyl)-3-(4-4- (trifluoromethoxy)phenoxy)quinoxaline-2- (trifluoromethoxy)phenolcarboxamide 9 3-(4-chloro-2-methylphenoxy)-N-(3- 4-chloro-2-methyl-sulfamoylphenyl)quinoxaline-2-carboxamide phenol 123-(2-fluoro-4-methoxyphenoxy)-N-(3- 2-fluoro-4-methoxy-phenolsulfamoylphenyl)quinoxaline-2-carboxamide 103-(2-(difluoromethoxy)phenoxy)-N-(3- 2-sulfamoylphenyl)quinoxaline-2-carboxamide (difluoromethoxy)phenol 73-(3-fluoro-4-methoxyphenoxy)-N-(3- 3-fluoro-4-methoxy-sulfamoylphenyl)quinoxaline-2-carboxamide phenol 15N-(3-sulfamoylphenyl)-3-(4-(2,2,2- 4-(2,2,2-trifluoroethoxy)phenoxy)quinoxaline-2- trifluoroethoxy)phenolcarboxamide 13 3-phenoxy-N-(3-sulfamoylphenyl)quinoxaline-2- phenolcarboxamide

Example 11 Preparation of2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide(61)

2-Chloroquinoline-3-carboxylic acid (250 mg, 1.20 mmol),3-aminobenzenesulfonamide (207.3 mg, 1.20 mmol) and HATU (457.8 mg, 1.20mmol) were combined in DMF (2.5 mL) and treated with 4-methylmorpholine(397.1 μL, 3.61 mmol). The reaction was heated at 60° C. for 12 hours.The reaction was cooled to 25° C. The precipitate was filtered to yieldN-(3-sulfamoylphenyl)-2-(triazolo[4,5-b]pyridin-3-yloxy)quinoline-3-carboxamideas a solid. ESI-MS m/z calc. 461.09, found 461.3 (M+1)+; Retention time:1.35 minutes (3 minutes run).

4-Fluoro-2-methoxy-phenol (6.17 μL, 0.05 mmol),N-(3-sulfamoylphenyl)-2-(triazolo[4,5-b]pyridin-3-yloxy)quinoline-3-carboxamide(25 mg, 0.05 mmol) and K₂CO₃ (22.46 mg, 0.16 mmol) were combined in DMF(0.5 mL) and heated at 90° C. for 1 h. The reaction was diluted with DMF(0.5 mL), filtered, and purified by reverse phase HPLC (30-99% CH₃CN/5mM aqueous HCl) to provide2-(4-fluoro-2-methoxy-phenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide(61) (7.95 mg, 30%) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 10.86(s, 1H), 8.73 (s, 1H), 8.40-8.35 (m, 1H), 8.07 (dd, J=7.8, 1.6 Hz, 1H),7.88 (td, J=4.4, 2.1 Hz, 1H), 7.72 (ddd, J=8.4, 6.9, 1.5 Hz, 1H),7.64-7.52 (m, 4H), 7.42 (s, 2H), 7.38 (dd, J=8.9, 6.0 Hz, 1H), 7.12 (dd,J=10.8, 2.9 Hz, 1H), 6.87 (td, J=8.5, 2.9 Hz, 1H), 3.70 (s, 3H),8.76-8.68 (m, 1H) ppm. ESI-MS m/z calc. 467.09, found 468.3 (M+1)+;Retention time: 1.78 minutes (3 minutes run).

The following compounds were prepared using a similar experimentalprocedure as described above for cmpd 61 fromN-(3-sulfamoylphenyl)-2-(triazolo[4,5-b]pyridin-3-yloxy)quinoline-3-carboxamideand the following alcohols.

Cmpd. No. Product name Phenol 66 2-(2-chloro-4-fluorophenoxy)-N-(3-2-chloro-4-fluoro-phenol sulfamoylphenyl)quinoline-3-carboxamide 632-(4-fluoro-2-methylphenoxy)-N-(3- 4-fluoro-2-methyl-phenolsulfamoylphenyl)quinoline-3-carboxamide 65 2-(2,4-difluorophenoxy)-N-(3-2,4-difluorophenol sulfamoylphenyl)quinoline-3-carboxamide 68N-(3-sulfamoylphenyl)-2-(4- 4-(trifluoromethoxy)-phenol(trifluoromethoxy)phenoxy)quinoline-3- carboxamide 712-(4-chloro-2-methylphenoxy)-N-(3- 4-chloro-2-methyl-phenolsulfamoylphenyl)quinoline-3-carboxamide 692-(2-chloro-4-methoxyphenoxy)-N-(3- 2-chloro-4-methoxy-phenolsulfamoylphenyl)quinoline-3-carboxamide 60 2-(4-fluorophenoxy)-N-(3-4-fluorophenol sulfamoylphenyl)quinoline-3-carboxamide 742-(2-(difluoromethoxy)phenoxy)-N-(3- 2-(difluoromethoxy)phenolsulfamoylphenyl)quinoline-3-carboxamide 722-(2,4-dimethoxyphenoxy)-N-(3- 2,4-dimethoxyphenolsulfamoylphenyl)quinoline-3-carboxamide 622-(3-fluoro-4-methoxyphenoxy)-N-(3- 3-fluoro-4-methoxy-phenolsulfamoylphenyl)quinoline-3-carboxamide 732-(4-chloro-2-methoxyphenoxy)-N-(3- 4-chloro-2-methoxy-phenolsulfamoylphenyl)quinoline-3-carboxamide 702-(2-fluoro-4-methoxyphenoxy)-N-(3- 2-fluoro-4-methoxy-phenolsulfamoylphenyl)quinoline-3-carboxamide 67N-(3-sulfamoylphenyl)-2-(4-(2,2,2- 4-(2,2,2-trifluoroethoxy)phenoltrifluoroethoxy)phenoxy)quinoline-3- carboxamide 642-phenoxy-N-(3-sulfamoylphenyl)quinoline-3- phenol carboxamide

Example 12 Preparation of3-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)quinoxaline-2-carboxamide(35)

A solution of 3-(4-fluorophenoxy)quinoxaline-2-carboxylic acid (42.6 mg,0.15 mmol), 2-methoxypyridin-4-amine (22.3 mg, 0.18 mmol), HATU (62.7mg, 0.16 mmol) and N-methylmorpholine (32.98 μL, 0.30 mmol) in NMP (0.5mL) was stirred at 25° C. for 16 hours. The reaction mixture was pouredinto water and extracted with ethyl acetate (3×). The organics werecombined, washed with water, brine, dried with Na₂SO₄, filtered througha short plug of silica and evaporated to dryness. The residue was takenup in HBr (0.5 mL of 33% w/v in acetic acid, 2.04 mmol) and heated at100° C. for 4 hours. The reaction mixture was poured into water andextracted with ethyl acetate (3×). The organics were combined,evaporated and purified by reverse phase HPLC using a gradient ofacetonitrile in water (1-99%) and HCl as a modifier to give3-(4-fluorophenoxy)-N-(2-oxo-1H-pyridin-4-yl)quinoxaline-2-carboxamide(35) (5.0 mg, 9%) as a pale yellow solid. ESI-MS m/z calc. 376.10, found377.3 (M+1)+; Retention time: 1.31 minutes (3 minutes run).

Example 13 Preparation of3-(3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamido)benzoic acid(36)

To ethyl 3-aminobenzoate (18.9 mg, 0.11 mmol) in DMF (0.3 mL) was added3-(4-fluoro-2-methoxy-phenoxy)quinoxaline-2-carboxylic acid (30 mg, 0.09mmol), HATU (54.4 mg, 0.14 mmol) and Et₃N (39.9 μL, 0.29 mmol). Thereaction is stirred at 50° C. for 2 hours. Lithium hydroxide (45 μL of4M, 0.18 mmol) was added and the reaction was stirred at 25° C.overnight. The reaction was filtered and purified by reverse phase HPLCusing a gradient of methanol in water (1-99%) and ammonium formate as amodifier to yield3-(3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamido)benzoic acid(36) (16.4 mg, 42%). ESI-MS m/z calc. 433.11, found 434.0 (M+1)+;Retention time: 1.56 minutes (2.5 minutes run). ¹H NMR (400 MHz,DMSO-d6) δ 11.10 (s, 1H), 8.39 (t, J=1.9 Hz, 1H), 8.18 (dd, J=8.0, 1.6Hz, 1H), 7.99-7.92 (m, 1H), 7.87-7.68 (m, 4H), 7.48 (t, J=7.9 Hz, 1H),7.35 (dd, J=8.8, 5.9 Hz, 1H), 7.16 (dd, J=10.7, 2.9 Hz, 1H), 6.88 (td,J=8.5, 2.9 Hz, 1H), 3.71 (s, 3H) ppm.

2-(3-(4-Fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamido)thiazole-4-carboxylicacid (37) was prepared using a similar experimental procedure asdescribed above for cmpd (36) from3-(4-fluoro-2-methoxy-phenoxy)quinoxaline-2-carboxylic acid and ethyl2-aminothiazole-4-carboxylate.

Analytical data for the compounds of the present invention is providedbelow in Table 2. Mass Spec (e.g., M+1 data in Table 2), final purityand retention times were determined by reverse phase HPLC using aKinetix C18 column (50×2.1 mm, 1.7 μm particle) from Phenomenex (pn:00B-4475-AN)), and a dual gradient run from 1-99% mobile phase B over 3minutes. Mobile phase A=H₂O (0.05% CF₃CO₂H). Mobile phase B=CH₃CN (0.05%CF₃CO₂H). Flow rate=2 mL/min, injection volume=3 μL, and columntemperature=50° C.

TABLE 2 Analytical Data LCMS Retention Cmpd. Time in No. minutes M + 1¹H-NMR (400 MHz) 1 1.49 439.5 (DMSO-d₆) δ 11.26 (s, 1H), 8.40 (s, 1H),8.21-8.16 (m, 1H), 7.97-7.74 (m, 5H), 7.66-7.60 (m, 2H), 7.45 (s, 2H),7.37 (ddd, J = 17.5, 12.0, 6.9 Hz, 4H) ppm. 2 1.49 469.3 (DMSO-d₆) δ11.27 (s, 1H), 8.42 (s, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.97-7.87 (m,1H), 7.86-7.71 (m, 3H), 7.68-7.56 (m, 2H), 7.44 (s, 2H), 7.34 (dd, J =8.7, 5.9 Hz, 1H), 7.16 (dd, J = 10.8, 2.9 Hz, 1H), 6.88 (ddd, J = 8.6,2.9 Hz, 1H), 3.71 (s, 3H) ppm. 3 1.94 505.5 4 1.79 485.5 5 1.76 457.3(DMSO-d₆) δ 11.32 (s, 1H), 8.47-8.37 (m, 1H), 8.27-8.15 (m, 1H),7.97-7.75 (m, 4H), 7.69-7.50 (m, 4H), 7.45 (s, 2H), 7.30-7.17 (m, 1H).[1], 1H NMR (400 MHz, DMSO-d6) ? 11.32 (s, 1H), 8.49-8.39 (m, 1H),8.28-8.17 (m, 1H), 7.96-7.76 (m, 4H), 7.70-7.52 (m, 4H), 7.45 (s, 2H),7.32-7.15 (m, 1H) ppm. 6 1.83 473.3 7 1.73 469.5 (DMSO-d₆) δ 11.24 (s,1H), 8.44-8.35 (m, 1H), 8.22-8.13 (m, 1H), 7.94-7.74 (m, 4H), 7.68-7.56(m, 2H), 7.45 (s, 2H), 7.35 (dd, J = 11.9, 2.8 Hz, 1H), 7.28 (t, J = 9.3Hz, 1H), 7.22-7.07 (m, 1H), 3.89 (s, 3H) ppm. 8 1.69 481.3 (DMSO-d₆) δ11.25 (s, 1H), 8.49-8.36 (m, 1H), 8.16 (dd, J = 7.9, 1.7 Hz, 1H),7.95-7.87 (m, 1H), 7.87-7.70 (m, 3H), 7.67-7.55 (m, 2H), 7.44 (s, 2H),7.20 (d, J = 8.7 Hz, 1H), 6.76 (d, J = 2.8 Hz, 1H), 6.59 (dd, J = 8.8,2.8 Hz, 1H), 3.81 (s, 3H), 3.68 (s, 3H) ppm. 9 1.92 469.5 (DMSO-d₆) δ11.29 (s, 1H), 8.47-8.36 (m, 1H), 8.33-8.11 (m, 1H), 7.91-7.76 (m, 4H),7.72-7.55 (m, 2H), 7.49 (d, J = 2.5 Hz, 1H), 7.45 (s, 2H), 7.42-7.32 (m,2H), 2.15 (s, 3H) ppm. 10 1.77 487.3 11 1.82 485.5 (DMSO-d₆) δ 11.27 (s,1H), 8.46-8.37 (m, 1H), 8.22-8.14 (m, 1H), 7.92-7.88 (m, 1H), 7.86-7.79(m, 2H), 7.79-7.75 (m, 1H), 7.65-7.60 (m, 2H), 7.44 (s, 2H), 7.35 (d, J= 8.5 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.12 (dd, J = 8.5, 2.4 Hz, 1H),3.72 (s, 3H) ppm. 12 1.75 469.5 13 1.7 421.3 14 1.81 453.5 15 1.88 519.5(DMSO-d₆) δ 11.25 (s, 1H), 8.44-8.34 (m, 1H), 8.18 (dd, J = 8.1, 1.6 Hz,1H), 7.94-7.72 (m, 4H), 7.66-7.56 (m, 2H), 7.44 (s, 2H), 7.38-7.26 (m,2H), 7.26-7.12 (m, 2H), 4.82 (q, J = 8.9 Hz, 2H) ppm. 16 1.59 483.2 171.96 470.5 (DMSO-d₆) δ 12.85 (s, 1H), 11.26 (s, 1H), 8.25-8.15 (m, 1H),8.04-7.96 (m, 2H), 7.95-7.88 (m, 2H), 7.88-7.76 (m, 3H), 7.58-7.44 (m,4H) ppm. 18 1.33 405.4 19 1.42 419.2 (DMSO-d₆) δ 11.55 (s, 1H), 9.04 (d,J = 2.4 Hz, 1H), 8.45 (dd, J = 8.6, 2.5 Hz, 1H), 8.20 (dd, J = 8.1, 1.6Hz, 1H), 8.14 (d, J = 8.6 Hz, 1H), 7.90-7.80 (m, 2H), 7.80-7.76 (m, 1H),7.35 (dd, J = 8.9, 5.1 Hz, 1H), 7.26 (dd, J = 9.4, 3.1 Hz, 1H),7.21-7.12 (m, 1H), 2.15 (s, 3H) ppm. 20 1.28 387.4 21 1.35 435.4(DMSO-d₆) δ 13.10 (s, 1H), 11.56 (s, 1H), 9.06 (d, J = 2.5 Hz, 1H), 8.45(dd, J = 8.6, 2.5 Hz, 1H), 8.22 (dd, J = 8.0, 1.6 Hz, 1H), 8.14 (d, J =8.6 Hz, 1H), 7.99-7.63 (m, 3H), 7.42 (t, J = 9.0 Hz, 1H), 7.10 (dd, J =12.4, 2.9 Hz, 1H), 6.94-6.84 (m, 1H), 3.83 (s, 3H) ppm. 22 1.51 485.4(DMSO-d₆) δ 11.54 (s, 1H), 9.05 (d, J = 2.4 Hz, 1H), 8.45 (dd, J = 8.6,2.5 Hz, 1H), 8.19 (dd, J = 8.1, 1.5 Hz, 1H), 8.14 (d, J = 8.6 Hz, 1H),7.96-7.65 (m, 3H), 7.38-7.27 (m, 2H), 7.27-7.08 (m, 2H), 4.82 (q, J =8.9 Hz, 2H) ppm. 23 1.45 451.2 24 1.38 453.4 (DMSO-d₆) δ 13.09 (s, 1H),11.55 (s, 1H), 9.06 (d, J = 2.5 Hz, 1H), 8.46 (dd, J = 8.6, 2.5 Hz, 1H),8.23 (dd, J = 8.1, 1.6 Hz, 1H), 8.14 (d, J = 8.6 Hz, 1H), 8.02-7.67 (m,3H), 7.61-7.50 (m, 1H), 7.50-7.36 (m, 3H), 7.36-6.88 (m, 1H) ppm. 251.54 435.2 26 1.3 447.2 (DMSO-d₆) δ 11.52 (s, 1H), 9.05 (d, J = 2.5 Hz,1H), 8.45 (dd, J = 8.6, 2.5 Hz, 1H), 8.18 (dd, J = 8.4, 1.6 Hz, 1H),8.14 (d, J = 8.6 Hz, 1H), 7.90-7.71 (m, 3H), 7.22 (d, J = 8.7 Hz, 1H),6.76 (d, J = 2.8 Hz, 1H), 6.60 (dd, J = 8.8, 2.8 Hz, 1H), 3.81 (s, 3H),3.68 (s, 3H) ppm. 27 1.32 435.4 (DMSO-d₆) δ 11.52 (s, 1H), 9.05 (d, J =2.5 Hz, 1H), 8.45 (dd, J = 8.6, 2.5 Hz, 1H), 8.23-8.16 (m, 1H), 8.14 (d,J = 8.6 Hz, 1H), 7.93-7.76 (m, 3H), 7.37 (dd, J = 11.9, 2.8 Hz, 1H),7.33-7.21 (m, 1H), 7.21-7.10 (m, 1H), 3.89 (s, 3H) ppm. 28 1.43 439.4 291.38 423.4 30 1.4 451.2 31 1.56 471.4 (DMSO-d₆) δ 13.2 9s, br. 1H, .11.51 (s, 1H), 9.04 (d, J = 2.4 Hz, 1H), 8.45 (dd, J = 8.6, 2.5 Hz, 1H),8.28-8.19 (m, 1H), 8.14 (d, J = 8.6 Hz, 1H), 7.92-7.79 (m, 3H), 7.52 (s,4H) ppm. 32 1.32 435.3 (DMSO-d₆) δ 13.12 (s br, 1H), 11.52 (s, 1H), 9.06(d, J = 2.3 Hz, 1H), 8.45 (dd, J = 8.6, 2.5 Hz, 1H), 8.20 (d, J = 7.8Hz, 1H), 8.14 (d, J = 8.6 Hz, 1H), 7.82 (ddd, J = 24.3, 15.6, 6.7 Hz,3H), 7.36 (dd, J = 8.8, 5.8 Hz, 1H), 7.16 (dd, J = 10.6, 2.8 Hz, 1H),6.88 (ddd, J = 8.5, 2.8 Hz, 1H), 3.70 (s, 3H) ppm. 33 1.42 471.4(Acetone-d₆) ? 10.97 (s, 1H), 8.69 (d, J = 5.6 Hz, 1H), 8.67 (d, J = 2.1Hz, 1H), 8.28 (dd, J = 5.6, 2.2 Hz, 1H), 8.18 (dd, J = 8.3, 1.5 Hz, 1H),7.96-7.88 (m, 1H), 7.87-7.81 (m, 1H), 7.80 (dd, J = 8.2, 1.5 Hz, 1H),7.60-7.46 (m, 4H) ppm. (DMSO-d₆) δ 11.58 (s, 1H), 8.67 (d, J = 5.5 Hz,1H), 8.51 (d, J = 2.1 Hz, 1H), 8.22 (dd, J = 8.4, 1.6 Hz, 1H), 7.99 (dd,J = 5.5, 2.2 Hz, 1H), 7.93-7.77 (m, 3H), 7.52 (s, 4H) ppm. 34 1.18 43535 1.31 377.3 36 1.56 434 (DMSO-d₆) δ 11.10 (s, 1H), 8.39 (t, J = 1.9Hz, 1H), 8.18 (dd, J = 8.0, 1.6 Hz, 1H), 7.99-7.92 (m, 1H), 7.87-7.68(m, 4H), 7.48 (t, J = 7.9 Hz, 1H), 7.35 (dd, J = 8.8, 5.9 Hz, 1H), 7.16(dd, J = 10.7, 2.9 Hz, 1H), 6.88 (td, J = 8.5, 2.9 Hz, 1H), 3.71 (s, 3H)ppm. 37 1.49 441 38 1.35 381.15 39 1.43 425.12 40 1.55 380.18 41 1.63458.24 42 1.56 431.22 43 1.43 380.18 44 1.35 460.19 45 1.65 458.24 461.73 468.11 47 1.68 430.18 48 1.61 430.18 49 1.32 430.15 50 1.85 416.1451 1.75 416.14 52 1.85 416.14 53 1.3 391.15 (DMSO-d₆) δ 12.42 (s, 1H),8.82 (d, J = 6.5 Hz, 2H), 8.33 (d, J = 6.5 Hz, 2H), 8.21 (d, J = 8.0 Hz,1H), 7.96-7.70 (m, 3H), 7.41 (dd, J = 8.8, 5.8 Hz, 1H), 7.17 (dd, J =10.7, 2.8 Hz, 1H), 6.89 (td, J = 8.5, 2.9 Hz, 1H), 3.70 (s, 4H) ppm. 541.27 391.15 55 1.86 415.13 56 1.85 415.16 (DMSO-d₆) δ 11.33 (s, 1H),8.28 (dd, J = 2.1, 1.1 Hz, 1H), 8.22-8.15 (m, 1H), 8.05 (ddd, J = 5.5,3.4, 2.2 Hz, 1H), 7.90-7.74 (m, 3H), 7.72-7.55 (m, 2H), 7.41-7.26 (m,1H), 7.16 (dd, J = 10.7, 2.9 Hz, 1H), 6.88 (td, J = 8.4, 2.7 Hz, 1H),3.71 (d, J = 0.9 Hz, 3H) ppm. 57 1.44 446.15 58 1.4 433.3 (DMSO-d₆) δ11.16 (s, 1H), 8.22-8.08 (m, 1H), 8.03-7.67 (m, 8H), 7.41-7.26 (m, 2H),7.16 (dd, J = 10.7, 2.9 Hz, 1H), 6.88 (td, J = 8.5, 2.9 Hz, 1H), 3.71(s, 3H) ppm. 59 1.6 433.2 60 1.61 438.5 (DMSO-d₆) δ 10.92 (s, 1H), 8.74(s, 1H), 8.38-8.34 (m, 1H), 8.08 (dd, J = 8.1, 1.4 Hz, 1H), 7.91-7.84(m, 1H), 7.74 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H),7.61-7.53 (m, 3H), 7.42 (s, 2H), 7.40-7.35 (m, 2H), 7.34-7.28 (m, 2H)ppm. 61 1.78 468.3 (DMSO-d₆) δ 10.86 (s, 1H), 8.73 (s, 1H), 8.40-8.35(m, 1H), 8.07 (dd, J = 7.8, 1.6 Hz, 1H), 7.88 (td, J = 4.4, 2.1 Hz, 1H),7.72 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.64-7.52 (m, 4H), 7.42 (s, 2H),7.38 (dd, J = 8.9, 6.0 Hz, 1H), 7.12 (dd, J = 10.8, 2.9 Hz, 1H), 6.87(td, J = 8.5, 2.9 Hz, 1H), 3.70 (s, 3H), 8.76-8.68 (m, 1H) ppm. 62 1.283468 63 1.36 452.2 64 1.26 420.2 65 1.318 456 66 1.375 472 67 1.419 51868 1.466 504 69 1.362 484 70 1.309 468 (DMSO-d₆) δ 10.95 (s, 1H), 8.74(s, 1H), 8.42-8.36 (m, 1H), 8.08 (dd, J = 8.0, 1.8 Hz, 1H), 7.92-7.85(m, 1H), 7.74 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H), 7.64 (d, J = 7.1 Hz, 1H),7.61-7.53 (m, 3H), 7.45-7.37 (m, 3H), 7.05 (dd, J = 12.4, 2.9 Hz, 1H),6.87 (ddd, J = 9.1, 3.0, 1.2 Hz, 1H), 3.82 (s, 3H) ppm. 71 1.456 468 721.66 480.3 73 1.425 484 (DMSO-d₆) δ 10.87 (s, 1H), 8.73 (s, 1H), 8.37(t, J = 1.4 Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.90-7.86 (m, 1H), 7.73(ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.60-7.53 (m,3H), 7.42 (s, 2H), 7.39 (d, J = 8.5 Hz, 1H), 7.28 (d, J = 2.4 Hz, 1H),7.11 (dd, J = 8.5, 2.4 Hz, 1H), 3.71 (s, 3H) ppm. 74 1.314 468 75 1.68452.2 (DMSO-d₆) δ 12.81 (s, 1H), 10.98 (s, 1H), 8.79 (s, 1H), 8.09 (dd,J = 8.1, 1.4 Hz, 1H), 8.02-7.93 (m, 2H), 7.89 (d, J = 8.8 Hz, 2H),7.82-7.71 (m, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.64-7.55 (m, 2H),7.55-7.45 (m, 1H), 7.27-7.13 (m, 1H) ppm. 76 1.72 420.2 77 1.67 456 781.67 472 79 1.49 518 80 1.43 504 (DMSO-d₆) δ 11.24 (s, 1H), 9.02 (d, J =2.5 Hz, 1H), 8.84 (s, 1H), 8.41 (dd, J = 8.6, 2.5 Hz, 1H), 8.17-8.04 (m,2H), 7.85-7.72 (m, 1H), 7.72-7.63 (m, 1H), 7.63-7.55 (m, 2H), 7.55-7.46(m, 1H), 7.30-7.14 (m, 1H) ppm.Assays for Detecting and Measuring Na_(V) Inhibition Properties ofCompoundsE-VIPR Optical Membrane Potential Assay Method with ElectricalStimulation

Sodium channels are voltage-dependent proteins that can be activated byinducing membrane voltage changes by applying electric fields. Theelectrical stimulation instrument and methods of use are described inIon Channel Assay Methods PCT/US01/21652, herein incorporated byreference and are referred to as E-VIPR. The instrument comprises amicrotiter plate handler, an optical system for exciting the coumarindye while simultaneously recording the coumarin and oxonol emissions, awaveform generator, a current- or voltage-controlled amplifier, and adevice for inserting electrodes in well. Under integrated computercontrol, this instrument passes user-programmed electrical stimulusprotocols to cells within the wells of the microtiter plate.

24 hours before the assay on E-VIPR, HEK cells expressing human Nav1.8were seeded in 384-well poly-lysine coated plates at 15,000-20,000 cellsper well. HEK cells were grown in media (exact composition is specificto each cell type and NaV subtype) supplemented with 10% FBS (FetalBovine Serum, qualified; GibcoBRL #16140-071) and 1% Pen-Strep(Penicillin-Streptomycin; GibcoBRL #15140-122). Cells were grown invented cap flasks, in 90% humidity and 5% CO₂.

Reagents and Solutions

100 mg/mL Pluronic F-127 (Sigma #P2443), in dry DMSO

Compound Plates: 384-well round bottom plate, e.g. Corning 384-wellPolypropylene Round Bottom #3656

Cell Plates: 384-well tissue culture treated plate, e.g. Greiner#781091-1B

10 mM DiSBAC₆(3) (Aurora #00-100-010) in dry DMSO

10 mM CC2-DMPE (Aurora #00-100-008) in dry DMSO

200 mM ABSC1 in H₂O

Bath1 buffer: Glucose 10 mM (1.8 g/L), Magnesium Chloride (Anhydrous), 1mM (0.095 g/L), Calcium Chloride, 2 mM (0.222 g/L), HEPES 10 mM (2.38g/L), Potassium Chloride, 4.5 mM (0.335 g/L), Sodium Chloride 160 mM(9.35 g/L).

Hexyl Dye Solution: Bath1 Buffer+0.5% β-cyclodextrin (make this prior touse, Sigma #C4767), 8 μM CC2-DMPE+2.5 μM DiSBAC₆(3). To make thesolution Added volume of 10% Pluronic F127 stock equal to volumes ofCC2-DMPE+DiSBAC₆(3). The order of preparation was first mix Pluronic andCC2-DMPE, then added DiSBAC₆(3) while vortexing, then addedBath1+β-Cyclodextrin.

Assay Protocol

1) Pre-spotted compounds (in neat DMSO) into compound plates. Vehiclecontrol (neat DMSO), the positive control (20 mM DMSO stock tetracaine,125 μM final in assay) and test compounds were added to each well at160× desired final concentration in neat DMSO. Final compound platevolume was 80 μL (80-fold intermediate dilution from 1 μL DMSO spot;160-fold final dilution after transfer to cell plate). Final DMSOconcentration for all wells in assay was 0.625%.

2) Prepared Hexyl Dye Solution.

3) Prepared cell plates. On the day of the assay, medium was aspiratedand cells were washed three times with 100 μL of Bath1 Solution,maintaining 25 μL residual volume in each well.

4) Dispensed 25 μL per well of Hexyl Dye Solution into cell plates.Incubated for 20-35 minutes at room temp or ambient conditions.

5) Dispensed 80 μL per well of Bath1 into compound plates. AcidYellow-17 (1 mM) was added and Potassium Chloride was altered from 4.5to 20 mM depending on the NaV subtype and assay sensitivity.

6) Washed cell plates three times with 100 μL per well of Bath1, leaving25 μL of residual volume. Then transferred 25 uL per well from CompoundPlates to Cell Plates. Incubated for 20-35 minutes at room temp/ambientcondition.

7) Read Plate on E-VIPR. Used the current-controlled amplifier todeliver stimulation wave pulses for 10 seconds and a scan rate of 200Hz. A pre-stimulus recording was performed for 0.5 seconds to obtain theun-stimulated intensities baseline. The stimulatory waveform wasfollowed by 0.5 seconds of post-stimulation recording to examine therelaxation to the resting state.

Data Analysis

Data was analyzed and reported as normalized ratios of emissionintensities measured in the 460 nm and 580 nm channels. The response asa function of time was reported as the ratios obtained using thefollowing formula:

${R(t)} = \frac{\left( {{intensity}_{460\mspace{14mu}{nm}} - {background}_{460\mspace{14mu}{nm}}} \right)}{\left( {{intensity}_{580\mspace{14mu}{nm}} - {background}_{580\mspace{14mu}{nm}}} \right)}$

The data was further reduced by calculating the initial (R_(i)) andfinal (R_(f)) ratios. These were the average ratio values during part orall of the pre-stimulation period, and during sample points during thestimulation period. The response to the stimulus R=R_(f)/R_(i) was thencalculated and reported as a function of time.

Control responses were obtained by performing assays in the presence ofa compound with the desired properties (positive control), such astetracaine, and in the absence of pharmacological agents (negativecontrol). Responses to the negative (N) and positive (P) controls werecalculated as above. The compound antagonist activity A is defined as:

$A = {\frac{R - P}{N - P}*100.}$where R is the ratio response of the test compound

Electrophysiology Assays for Na_(V) Activity and Inhibition of TestCompounds

Patch clamp electrophysiology was used to assess the efficacy andselectivity of sodium channel blockers in dorsal root ganglion neurons.Rat neurons were isolated from the dorsal root ganglions and maintainedin culture for 2 to 10 days in the presence of NGF (50 ng/ml) (culturemedia consisted of NeurobasalA supplemented with B27, glutamine andantibiotics). Small diameter neurons (nociceptors, 8-12 μm in diameter)were visually identified and probed with fine tip glass electrodesconnected to an amplifier (Axon Instruments). The “voltage clamp” modewas used to assess the compound's IC₅₀ holding the cells at −60 mV. Inaddition, the “current clamp” mode was employed to test the efficacy ofthe compounds in blocking action potential generation in response tocurrent injections. The results of these experiments contributed to thedefinition of the efficacy profile of the compounds.

The exemplified compounds in Table 1 herein are active against Nav1.8sodium channels as measured using the assays described herein and aspresented in Table 3 below.

TABLE 3 Nav1.8 IC₅₀ activity Cmpd. No. Na_(v)1.8 IC₅₀ (μM) 1 0.027 20.006 3 0.014 4 0.004 5 0.013 6 0.003 7 0.042 8 0.006 9 0.014 10 0.03611 0.005 12 0.022 13 0.092 14 0.007 15 0.066 16 0.022 17 0.044 18 0.2519 0.086 20 1.08 21 0.235 22 0.18 23 0.019 24 0.34 25 0.056 26 0.046 270.185 28 0.051 29 0.185 30 0.069 31 0.015 32 0.083 33 0.007 34 0.016 350.074 36 0.46 37 0.45 38 1.215 39 2.6 40 1.7 41 2.2 42 0.096 43 0.22 440.425 45 1.65 46 0.001 47 0.13 48 0.086 49 0.585 50 1.25 51 0.037 52 2.453 0.022 54 0.08 55 0.046 56 0.03 57 0.019 58 0.031 59 0.18 60 0.017 610.011 62 0.03 63 0.008 64 0.081 65 0.011 66 0.002 67 0.061 68 0.013 690.015 70 0.034 71 0.014 72 0.026 73 0.031 74 0.024 75 0.275 76 0.315 770.975 78 0.55 79 0.096 80 0.255

IonWorks assays.

This assay was performed to determine the activity for the compounds ofthe present invention against non Na_(V)1.8 channels. Sodium currentswere recorded using the automated patch clamp system, IonWorks(Molecular Devices Corporation, Inc.). Cells expressing Na_(V) subtypeswere harvested from tissue culture and placed in suspension at 0.5-4million cells per mL Bath1. The IonWorks instrument measured changes insodium currents in response to applied voltage clamp similarly to thetraditional patch clamp assay, except in a 384-well format. Using theIonWorks, dose-response relationships were determined in voltage clampmode by depolarizing the cell from the experiment specific holdingpotential to a test potential of about 0 mV before and followingaddition of the test compound. The influence of the compound on currentswere measured at the test potential.

Many modifications and variations of the embodiments described hereinmay be made without departing from the scope, as is apparent to thoseskilled in the art. The specific embodiments described herein areoffered by way of example only.

We claim:
 1. A compound of formula I

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence: Y is N; Ar¹ is a 5-6 membered aromatic monocyclicring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur, wherein said ring is optionally fused to a 5-memberedmonocyclic aromatic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, wherein Ar¹ has m substituents, eachindependently selected from —WR^(W); m is 0, 1, 2, 3, 4, or 5; W is abond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen, wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkylmay be replaced with —O—, —CO—, —S—, —SO—, or —SO₂—; R^(W) is absent, H,halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, OCF₃, or a 3-6 membered saturated,partially unsaturated, or fully unsaturated monocyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur; R′is C₁-C₆ alkyl; R¹ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆alkyl is substituted with 0-6 halogen and wherein up to two non-adjacentCH₂ units of said C₁-C₆ alkyl may be replaced with —O—; R² is H,halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen, wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—; R³ is H, halogen, CN, or C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up totwo non-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—;R⁴ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen, wherein up to two non-adjacent CH₂ unitsof said C₁-C₆ alkyl may be replaced with —O—; R⁵ is H, halogen, CN, or—X—R^(X); R^(5′) is H, halogen, CN, or —X—R^(X); R⁶ is H, halogen, CN,or —X—R^(X); R^(6′) is H, halogen, CN, or —X—R^(X); R⁷ is H, halogen,CN, or —X—R^(X); X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen, wherein up to two non-adjacent CH₂ unitsof said C₁-C₆ alkyl may be replaced with —O—; and R^(X) is absent, H, orC₃-C₈ cycloaliphatic, wherein up to two non-adjacent CH₂ units of saidC₃-C₈ cycloaliphatic may be replaced with —O— and said C₃-C₈cycloaliphatic is substituted with 0-3 substituents selected fromhalogen and C₁-C₄ alkyl.
 2. The compound according to claim 1, whereinthe compound has formula I-A:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence: Y is N; A₁ is a 5-6 membered aromatic ring having0-4 heteroatoms, independently selected from nitrogen, oxygen, orsulfur; m is 0, 1, 2, 3, 4, or 5; W is a bond or C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—,—CO—, —S—, —SO—, or —SO₂—; R^(W) is absent, H, halogen, OH, NH₂, NHR′,NO₂, CN, CF₃, OCF₃, or a 3-6 membered saturated, partially unsaturated,or fully unsaturated monocyclic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; R′ is C₁-C₆alkyl; R¹ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen and wherein up to two non-adjacent CH₂units of said C₁-C₆ alkyl may be replaced with —O—; R² is H, halogen,CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen, wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkylmay be replaced with —O—; R³ is H, halogen, CN, or C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—; R⁴is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen, wherein up to two non-adjacent CH₂ unitsof said C₁-C₆ alkyl may be replaced with —O—; R⁵ is H, halogen, CN, or—X—R^(X); R^(5′) is H, halogen, CN, or —X—R^(X); R⁶ is H, halogen, CN,or —X—R^(X); R^(6′) is H, halogen, CN, or —X—R^(X); R⁷ is H, halogen,CN, or —X—R^(X); X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen, wherein up to two non-adjacent CH₂ unitsof said C₁-C₆ alkyl may be replaced with —O—; and R^(X) is absent, H, orC₃-C₈ cycloaliphatic, wherein up to two non-adjacent CH₂ units of saidC₃-C₈ cycloaliphatic may be replaced with —O— and said C₃-C₈cycloaliphatic is substituted with 0-3 substituents selected fromhalogen and C₁-C₄ alkyl.
 3. The compound or pharmaceutically acceptablesalt according to claim 2, wherein R¹, R², R³ and R⁴ are H.
 4. Thecompound or pharmaceutically acceptable salt according to claim 2,wherein R⁵ and R⁷ are each independently halogen, or —X—R^(X) andR^(5′), R⁶, and R^(6′) are each H; and ring A₁ is:


5. The compound or pharmaceutically acceptable salt according to claim4, wherein R⁵ and R⁷ are each independently F, Cl, CH₃, OCF₃, or OCH₃;and ring A₁ is:


6. The compound or pharmaceutically acceptable salt according to claim5, wherein ring A is:


7. The compound according to claim 1, wherein the compound has formulaI-B:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence: Y is N; m is 0, 1, 2, 3, 4, or 5; W is a bond orC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen,wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O—, —CO—, —S—, —SO—, or —SO₂—; R^(W) is absent, H,halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, OCF₃, or a 3-6 membered saturated,partially unsaturated, or fully unsaturated monocyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur; R′is C₁-C₆ alkyl; R¹ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆alkyl is substituted with 0-6 halogen and wherein up to two non-adjacentCH₂ units of said C₁-C₆ alkyl may be replaced with —O—; R² is H,halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen, wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—; R³ is H, halogen, CN, or C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up totwo non-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—;R⁴ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen, wherein up to two non-adjacent CH₂ unitsof said C₁-C₆ alkyl may be replaced with —O—; R⁵ is H, halogen, CN, or—X—R^(X); R^(5′) is H, halogen, CN, or —X—R^(X); R⁶ is H, halogen, CN,or —X—R^(X); R^(6′) is H, halogen, CN, or —X—R^(X); R⁷ is H, halogen,CN, or —X—R^(X); X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen, wherein up to two non-adjacent CH₂ unitsof said C₁-C₆ alkyl may be replaced with —O—; and R^(X) is absent, H, orC₃-C₈ cycloaliphatic, wherein up to two non-adjacent CH₂ units of saidC₃-C₈ cycloaliphatic may be replaced with —O— and said C₃-C₈cycloaliphatic is substituted with 0-3 substituents selected fromhalogen and C₁-C₄ alkyl.
 8. The compound according to claim 7, whereinthe compound has formula I-B-2:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence: Y is N; m is 0, 1, 2, 3, 4, or 5; W is a bond orC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen,wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O— —CO—, —S—, —SO—, or —SO₂—; R^(W) is absent, H,halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, OCF₃, or a 3-6 membered saturated,partially unsaturated, or fully unsaturated monocyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur; R′is C₁-C₆ alkyl; R¹ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆alkyl is substituted with 0-6 halogen and wherein up to two non-adjacentCH₂ units of said C₁-C₆ alkyl may be replaced with —O—; R² is H,halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen, wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—; R³ is H, halogen, CN, or C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up totwo non-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—;R⁴ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen, wherein up to two non-adjacent CH₂ unitsof said C₁-C₆ alkyl may be replaced with —O—; R⁷ is halogen, CN, or—X—R^(X); X is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen, wherein up to two non-adjacent CH₂ unitsof said C₁-C₆ alkyl may be replaced with —O—; and R^(X) is absent, H, orC₃-C₈ cycloaliphatic, wherein up to two non-adjacent CH₂ units of saidC₃-C₈ cycloaliphatic may be replaced with —O— and said C₃-C₈cycloaliphatic is substituted with 0-3 substituents selected fromhalogen and C₁-C₄ alkyl.
 9. The compound according to claim 7, whereinthe compound has formula I-B-4:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence: Y is N; m is 0, 1, 2, 3, 4, or 5; W is a bond orC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen,wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O—, —CO—, —S—, —SO—, or —SO₂—; R^(W) is absent, H,halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, OCF₃, or a 3-6 membered saturated,partially unsaturated, or fully unsaturated monocyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur; R′is C₁-C₆ alkyl; R¹ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆alkyl is substituted with 0-6 halogen and wherein up to two non-adjacentCH₂ units of said C₁-C₆ alkyl may be replaced with —O—; R² is H,halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with0-6 halogen, wherein up to two non-adjacent CH₂ units of said C₁-C₆alkyl may be replaced with —O—; R³ is H, halogen, CN, or C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up totwo non-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—;R⁴ is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen, wherein up to two non-adjacent CH₂ unitsof said C₁-C₆ alkyl may be replaced with —O—; R⁵ is halogen, CN, or—X—R^(X); R⁷ is halogen, CN, or —X—R^(X); X is a bond or C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen, wherein up totwo non-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—;and R^(X) is absent, H, or C₃-C₈ cycloaliphatic, wherein up to twonon-adjacent CH₂ units of said C₃-C₈ cycloaliphatic may be replaced with—O— and said C₃-C₈ cycloaliphatic is substituted with 0-3 substituentsselected from halogen and C₁-C₄ alkyl.
 10. The compound according toclaim 1, wherein the compound has formula I-E:

or a pharmaceutically acceptable salt thereof, wherein, independentlyfor each occurrence: Y is N; A₁ and A₂, together, form an 8-9 memberedaromatic, bicyclic ring, wherein each ring contains 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; m is 0, 1, 2,3, 4, or 5; W is a bond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen, wherein up to two non-adjacent CH₂ unitsof said C₁-C₆ alkyl may be replaced with —O—, —CO—, —S—, —SO—, or —SO₂—;R^(W) is absent, H, halogen, OH, NH₂, NHR′, NO₂, CN, CF₃, OCF₃, or a 3-6membered saturated, partially unsaturated, or fully unsaturatedmonocyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur; R′ is C₁-C₆ alkyl; R¹ is H, halogen, CN, orC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen andwherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O—; R² is H, halogen, CN, or C₁-C₆ alkyl wherein saidC₁-C₆ alkyl is substituted with 0-6 halogen, wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—; R³is H, halogen, CN, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen, wherein up to two non-adjacent CH₂ unitsof said C₁-C₆ alkyl may be replaced with —O—; R⁴ is H, halogen, CN, orC₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogen,wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkyl may bereplaced with —O—; R⁵ is H, halogen, CN, or —X—R^(X); R^(5′) is H,halogen, CN, or —X—R^(X); R⁶ is H, halogen, CN, or —X—R^(X); R^(6′) isH, halogen, CN, or —X—R^(X); R⁷ is H, halogen, CN, or —X—R^(X); X is abond or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen, wherein up to two non-adjacent CH₂ units of said C₁-C₆ alkylmay be replaced with —O—; and R^(X) is absent, H, or C₃-C₈cycloaliphatic, wherein up to two non-adjacent CH₂ units of said C₃-C₈cycloaliphatic may be replaced with —O— and said C₃-C₈ cycloaliphatic issubstituted with 0-3 substituents selected from halogen and C₁-C₄ alkyl.11. The compound or pharmaceutically acceptable salt according to claim10, wherein R⁵ and R⁷ are each independently halogen, or —X—R^(X) andR^(5′), R⁶, and R^(6′) are each H; and A₁ and A₂, together, are:


12. The compound or pharmaceutically acceptable salt according to claim11, wherein R⁵ and R⁷ are each independently F, Cl, CH₃, OCF₃, or OCH₃;and A₁ and A₂, together with WR^(W), are:


13. The compound or pharmaceutically acceptable salt according to claim11, wherein ring A is:


14. The compound or pharmaceutically acceptable salt according to claim1, wherein R³ is H, halogen or C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen; and R⁴ is H, halogen or C₁-C₆ alkylwherein said C₁-C₆ alkyl is substituted with 0-6 halogen.
 15. Thecompound or pharmaceutically acceptable salt according to claim 14,wherein R³ is t-butyl, Cl, CF₃ or CF₂CF₃; and R⁴ is CF₃.
 16. Thecompound or pharmaceutically acceptable salt according to claim 15,wherein R⁵ and R⁷ are each independently F, Cl, CH₃, OCF₃, or OCH₃. 17.The compound or pharmaceutically acceptable salt according to claim 1,wherein R¹ is H or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen; and R² is H, halogen, or C₁-C₆ alkyl wherein saidC₁-C₆ alkyl is substituted with 0-6 halogen and wherein one CH₂ unit ofsaid C₆ alkyl is replaced with —O—.
 18. The compound or pharmaceuticallyacceptable salt according to claim 17, wherein R¹ is CF₃ and R² is F,Cl, CF₃ or OCF₃.
 19. The compound or pharmaceutically acceptable saltaccording to claim 1, wherein R¹, R², R³ and R⁴ are H.
 20. The compoundor pharmaceutically acceptable salt according to claim 1, wherein R⁵ andR⁷ are each independently halogen, or —X—R^(X) and R^(5′), R⁶, andR^(6′) are each H.
 21. The compound or pharmaceutically acceptable saltaccording to claim 1, wherein ring A is:


22. The compound of claim 1, selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 23. The compoundaccording to claim 22, selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 24. A pharmaceuticalcomposition comprising a therapeutically effective amount of thecompound or a pharmaceutically acceptable salt thereof of claim 23 andone or more pharmaceutically acceptable carriers or vehicles.
 25. Apharmaceutical composition comprising a therapeutically effective amountof the compound or a pharmaceutically acceptable salt thereof of claim 1and one or more pharmaceutically acceptable carriers or vehicles.
 26. Amethod of inhibiting a voltage-gated sodium channel in a subjectcomprising administering to the subject a compound or a pharmaceuticallyacceptable salt thereof of claim
 1. 27. A method of inhibiting avoltage-gated sodium channel in a subject comprising administering tothe subject the pharmaceutical composition of claim
 24. 28. A method ofinhibiting voltage-gated sodium channel Na_(V)1.8 in a subjectcomprising administering to the subject the compound of claim 1, or apharmaceutically acceptable salt thereof.
 29. The method of claim 28,wherein the subject is suffering from chronic pain, gut pain,neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain,cancer pain, or idiopathic pain.
 30. The method of claim 29, wherein thesubject is suffering from inflammatory pain.
 31. The method of claim 29,wherein the subject is suffering from neuropathic pain.
 32. The methodof claim 29, wherein the subject is suffering from musculoskeletal pain.33. The method of claim 32, wherein the musculoskeletal pain comprisesosteoarthritis pain.
 34. A method of inhibiting voltage-gated sodiumchannel Na_(V)1.8 in a subject comprising administering to the subjectthe compound of claim 23, or a pharmaceutically acceptable salt thereof.35. The method of claim 34, wherein the subject is suffering fromchronic pain, gut pain, neuropathic pain, musculoskeletal pain, acutepain, inflammatory pain, cancer pain, or idiopathic pain.